Sixth Edition

■■ -■■
.,.■■.c• .,.■■,.f.
■■ ■■
.,.■■.c• .,.■■,.f.
ALBERTS JOHNSON LEWIS MORGAN RAFF ROBERTS WALTER
 xxi

Detailed Contents

Chapter 1 Cells and Genomes 1 The Frog and the Zebrafish Provide Accessible Models for
Vertebrate Development 35
The Universal Features of Cells on Earth 2 The Mouse Is the Predominant Mammalian Model Organism 35

Genomes
All Cells Store Their Hereditary Information in the Same Linear Humans Report on Their Own Peculiarities 36
Chemical Code: DNA 2 We Are All Different in Detail 38
Background

All Cells Replicate Their Hereditary Information by Templated To Understand Cells and Organisms Will Require Mathematics,
Polymerization 3 Computers, and Quantitative Information 38
All Cells Transcribe Portions of Their Hereditary Information into Summary 39
the Same Intermediary Form: RNA 4 Problems 39
All Cells Use Proteins as Catalysts 5 References 41
All Cells Translate RNA into Protein in the Same Way 6
Each Protein Is Encoded by a Specific Gene 7 Chapter 2 Cell Chemistry and Bioenergetics 43
Life Requires Free Energy 8
All Cells Function as Biochemical Factories Dealing with the Same The Chemical Components of a Cell 43
Basic Molecular Building Blocks 8 Water Is Held Together by Hydrogen Bonds 44
All Cells Are Enclosed in a Plasma Membrane Across Which Four Types of Noncovalent Attractions Help Bring Molecules
Nutrients and Waste Materials Must Pass 8 Together in Cells 44
A Living Cell Can Exist with Fewer Than 500 Genes 9 Some Polar Molecules Form Acids and Bases in Water 45
A Cell Is Formed from Carbon Compounds 47
Summary 10
Cells Contain Four Major Families of Small Organic Molecules 47
The Diversity of Genomes and the Tree of Life 10 The Chemistry of Cells Is Dominated by Macromolecules with
Cells Can Be Powered by a Variety of Free-Energy Sources 10 Remarkable Properties 47
Some Cells Fix Nitrogen and Carbon Dioxide for Others 12 Noncovalent Bonds Specify Both the Precise Shape of a
The Greatest Biochemical Diversity Exists Among Prokaryotic Cells 12 Macromolecule and Its Binding to Other Molecules 49
The Tree of Life Has Three Primary Branches: Bacteria, Archaea, Summary 50
and Eukaryotes 14 Catalysis and the Use of Energy by Cells 51
Some Genes Evolve Rapidly; Others Are Highly Conserved 15 Cell Metabolism Is Organized by Enzymes 51
Most Bacteria and Archaea Have 1000–6000 Genes 16 Biological Order Is Made Possible by the Release of Heat Energy
Genomes

New Genes Are Generated from Preexisting Genes 16 from Cells 52

Gene Duplications Give Rise to Families of Related Genes Within Cells Obtain Energy by the Oxidation of Organic Molecules 54
a Single Cell 17 Oxidation and Reduction Involve Electron Transfers 55
Genes Can Be Transferred Between Organisms, Both in the Enzymes Lower the Activation-Energy Barriers That Block
Laboratory and in Nature 18 Chemical Reactions 57
Sex Results in Horizontal Exchanges of Genetic Information Enzymes Can Drive Substrate Molecules Along Specific Reaction
Within a Species 19 Pathways 58
The Function of a Gene Can Often Be Deduced from Its Sequence 20 How Enzymes Find Their Substrates: The Enormous Rapidity of
More Than 200 Gene Families Are Common to All Three Primary Molecular Motions 59
Branches of the Tree of Life 20 The Free-Energy Change for a Reaction, ∆G, Determines Whether
Mutations Reveal the Functions of Genes 21 It Can Occur Spontaneously 60
Molecular Biology Began with a Spotlight on E. coli 22 The Concentration of Reactants Influences the Free-Energy
Summary 22 Change and a Reaction’s Direction 61
The Standard Free-Energy Change, ∆G°, Makes It Possible
Genetic Information in Eukaryotes 23 to Compare the Energetics of Different Reactions 61
Eukaryotic Cells May Have Originated as Predators 24 The Equilibrium Constant and ∆G° Are Readily Derived from
Genomes

Modern Eukaryotic Cells Evolved from a Symbiosis 25 Each Other 62

Eukaryotes Have Hybrid Genomes 27 The Free-Energy Changes of Coupled Reactions Are Additive 63
Eukaryotic Genomes Are Big 28 Activated Carrier Molecules Are Essential for Biosynthesis 63
Eukaryotic Genomes Are Rich in Regulatory DNA 29 The Formation of an Activated Carrier Is Coupled to an
The Genome Defines the Program of Multicellular Development 29 Energetically Favorable Reaction 64
Many Eukaryotes Live as Solitary Cells 30 ATP Is the Most Widely Used Activated Carrier Molecule 65
A Yeast Serves as a Minimal Model Eukaryote 30 Energy Stored in ATP Is Often Harnessed to Join Two Molecules
The Expression Levels of All the Genes of An Organism Together 65
Can Be Monitored Simultaneously 32 NADH and NADPH Are Important Electron Carriers 67
Arabidopsis Has Been Chosen Out of 300,000 Species There Are Many Other Activated Carrier Molecules in Cells 68
As a Model Plant 32 The Synthesis of Biological Polymers Is Driven by ATP Hydrolysis 70
The World of Animal Cells Is Represented By a Worm, a Fly, Summary 73
a Fish, a Mouse, and a Human 33 HOW CELLS OBTAIN ENERGY FROM FOOD 73
Studies in Drosophila Provide a Key to Vertebrate Development 33 Glycolysis Is a Central ATP-Producing Pathway 74
The Vertebrate Genome Is a Product of Repeated Duplications 34 Fermentations Produce ATP in the Absence of Oxygen 75
xxii DETAILED CONTENTS

Glycolysis Illustrates How Enzymes Couple Oxidation to Energy The Regulation of the Src Protein Kinase Reveals How a Protein
Storage 76 Can Function as a Microprocessor 155
Organisms Store Food Molecules in Special Reservoirs 78 Proteins That Bind and Hydrolyze GTP Are Ubiquitous Cell
Most Animal Cells Derive Their Energy from Fatty Acids Between Regulators 156
Meals 81 Regulatory Proteins GAP and GEF Control the Activity of GTP-
Sugars and Fats Are Both Degraded to Acetyl CoA in Mitochondria 81 Binding Proteins by Determining Whether GTP or GDP
The Citric Acid Cycle Generates NADH by Oxidizing Acetyl Is Bound 157
Groups to CO2 82 Proteins Can Be Regulated by the Covalent Addition of Other
Electron Transport Drives the Synthesis of the Majority of the ATP Proteins 157
in Most Cells 84 An Elaborate Ubiquitin-Conjugating System Is Used to Mark
Amino Acids and Nucleotides Are Part of the Nitrogen Cycle 85 Proteins 158
Metabolism Is Highly Organized and Regulated 87 Protein Complexes with Interchangeable Parts Make Efficient
Summary 88 Use of Genetic Information 159
Problems 88 A GTP-Binding Protein Shows How Large Protein Movements
References 108 Can Be Generated 160
Motor Proteins Produce Large Movements in Cells 161
Chapter 3 Proteins 109 Membrane-Bound Transporters Harness Energy to Pump
Molecules Through Membranes 163
THE SHAPE AND STRUCTURE OF PROTEINS 109 Proteins Often Form Large Complexes That Function as Protein
The Shape of a Protein Is Specified by Its Amino Acid Sequence 109 Machines 164
Proteins Fold into a Conformation of Lowest Energy 114 Scaffolds Concentrate Sets of Interacting Proteins 164
The α Helix and the β Sheet Are Common Folding Patterns 115 Many Proteins Are Controlled by Covalent Modifications That
Protein Domains Are Modular Units from Which Larger Proteins Direct Them to Specific Sites Inside the Cell 165
Are Built 117 A Complex Network of Protein Interactions Underlies Cell Function 166
Few of the Many Possible Polypeptide Chains Will Be Useful Summary 169
to Cells 118 Problems 170
Proteins Can Be Classified into Many Families 119 References 172
Some Protein Domains Are Found in Many Different Proteins 121
Certain Pairs of Domains Are Found Together in Many Proteins 122
The Human Genome Encodes a Complex Set of Proteins, Chapter 4 DNA, Chromosomes, and Genomes 173
Background

Revealing That Much Remains Unknown 122 THE STRUCTURE AND FUNCTION OF DNA 173
Larger Protein Molecules Often Contain More Than One A DNA Molecule Consists of Two Complementary Chains of
Polypeptide Chain 123 Nucleotides 175
Some Globular Proteins Form Long Helical Filaments 123 The Structure of DNA Provides a Mechanism for Heredity 177
Many Protein Molecules Have Elongated, Fibrous Shapes 124 In Eukaryotes, DNA Is Enclosed in a Cell Nucleus 178
Proteins Contain a Surprisingly Large Amount of Intrinsically Summary 179
Disordered Polypeptide Chain 125
Covalent Cross-Linkages Stabilize Extracellular Proteins 127 CHROMOSOMAL DNA AND ITS PACKAGING IN THE
Protein Molecules Often Serve as Subunits for the Assembly CHROMATIN FIBER 179
of Large Structures 127 Eukaryotic DNA Is Packaged into a Set of Chromosomes 180
Many Structures in Cells Are Capable of Self-Assembly 128 Chromosomes Contain Long Strings of Genes 182
Assembly Factors Often Aid the Formation of Complex Biological The Nucleotide Sequence of the Human Genome Shows How
Structures 130 Our Genes Are Arranged 183
Amyloid Fibrils Can Form from Many Proteins 130 Each DNA Molecule That Forms a Linear Chromosome Must
Amyloid Structures Can Perform Useful Functions in Cells 132 Contain a Centromere, Two Telomeres, and Replication
Many Proteins Contain Low-complexity Domains that Can Form Origins 185
“Reversible Amyloids” 132 DNA Molecules Are Highly Condensed in Chromosomes 187
Summary 134 Nucleosomes Are a Basic Unit of Eukaryotic Chromosome
PROTEIN FUNCTION 134 Structure 187
All Proteins Bind to Other Molecules 134 The Structure of the Nucleosome Core Particle Reveals How
The Surface Conformation of a Protein Determines Its Chemistry 135 DNA Is Packaged 188
Sequence Comparisons Between Protein Family Members Nucleosomes Have a Dynamic Structure, and Are Frequently
Highlight Crucial Ligand-Binding Sites 136 Subjected to Changes Catalyzed by ATP-Dependent
Proteins Bind to Other Proteins Through Several Types of Chromatin Remodeling Complexes 190
Genomes

Interfaces 137 Nucleosomes Are Usually Packed Together into a Compact

Antibody Binding Sites Are Especially Versatile 138 Chromatin Fiber 191
The Equilibrium Constant Measures Binding Strength 138 Summary 193
Enzymes Are Powerful and Highly Specific Catalysts 140 CHROMATIN STRUCTURE AND FUNCTION 194
Substrate Binding Is the First Step in Enzyme Catalysis 141
Heterochromatin Is Highly Organized and Restricts Gene
Enzymes Speed Reactions by Selectively Stabilizing Transition
Expression 194
States 141
The Heterochromatic State Is Self-Propagating 194
Enzymes Can Use Simultaneous Acid and Base Catalysis 144
Lysozyme Illustrates How an Enzyme Works 144 The Core Histones Are Covalently Modified at Many Different Sites 196
Tightly Bound Small Molecules Add Extra Functions to Proteins 146 Chromatin Acquires Additional Variety Through the Site-Specific
Multienzyme Complexes Help to Increase the Rate of Cell Insertion of a Small Set of Histone Variants 198
Metabolism 148 Covalent Modifications and Histone Variants Act in Concert to
The Cell Regulates the Catalytic Activities of Its Enzymes 149 Control Chromosome Functions 198
Allosteric Enzymes Have Two or More Binding Sites That Interact 151 A Complex of Reader and Writer Proteins Can Spread Specific
Two Ligands Whose Binding Sites Are Coupled Must Reciprocally Chromatin Modifications Along a Chromosome 199
Affect Each Other’s Binding 151 Barrier DNA Sequences Block the Spread of Reader–Writer
Symmetric Protein Assemblies Produce Cooperative Allosteric Complexes and thereby Separate Neighboring Chromatin
Transitions 152 Domains 202
Many Changes in Proteins Are Driven by Protein Phosphorylation 153 The Chromatin in Centromeres Reveals How Histone Variants
A Eukaryotic Cell Contains a Large Collection of Protein Kinases Can Create Special Structures 203
and Protein Phosphatases 154 Some Chromatin Structures Can Be Directly Inherited 204
 DETAILED CONTENTS xxiii

Experiments with Frog Embryos Suggest that both ActivatingReplication The Proteins at a Replication Fork Cooperate to Form a
and Repressive Chromatin Structures Can Be Inherited Replication Machine 249
Epigenetically DNA Repair
205 A Strand-Directed Mismatch Repair System Removes Replication
Chromatin Structures Are Important for Eukaryotic Chromosome Errors That Escape from the Replication Machine 250
Function 206 DNA Topoisomerases Prevent DNA Tangling During Replication 251
Summary 207 DNA Replication Is Fundamentally Similar in Eukaryotes and
THE GLOBAL STRUCTURE OF CHROMOSOMES 207 Bacteria 253
Chromosomes Are Folded into Large Loops of Chromatin 207 Summary 254
Genomes

Polytene Chromosomes Are Uniquely Useful for Visualizing THE INITIATION AND COMPLETION OF DNA REPLICATION
Chromatin Structures 208 IN CHROMOSOMES 254
There Are Multiple Forms of Chromatin 210 DNA Synthesis Begins at Replication Origins 254
Chromatin Loops Decondense When the Genes Within Them Bacterial Chromosomes Typically Have a Single Origin of DNA

Replicaiton and
Are Expressed 211 Replication 255
Chromatin Can Move to Specific Sites Within the Nucleus to Eukaryotic Chromosomes Contain Multiple Origins of Replication 256
Alter Gene Expression 212 In Eukaryotes, DNA Replication Takes Place During Only One

Replication Cell Cycle

Networks of Macromolecules Form a Set of Distinct Biochemical Part of the Cell Cycle 258
Environments inside the Nucleus 213 Different Regions on the Same Chromosome Replicate at Distinct
Mitotic Chromosomes Are Especially Highly Condensed 214 Times in S Phase 258
Summary 216 A Large Multisubunit Complex Binds to Eukaryotic Origins of
How Genomes Evolve 216 Replication 259
Genome Variation

Genome Comparisons Reveal Functional DNA Sequences by Features of the Human Genome That Specify Origins of
their Conservation Throughout Evolution 217 Replication Remain to Be Discovered 260
Genome Alterations Are Caused by Failures of the Normal New Nucleosomes Are Assembled Behind the Replication Fork 261
Mechanisms for Copying and Maintaining DNA, as well as Telomerase Replicates the Ends of Chromosomes 262
by Transposable DNA Elements 217 Telomeres Are Packaged Into Specialized Structures That
The Genome Sequences of Two Species Differ in Proportion to Protect the Ends of Chromosomes 263
the Length of Time Since They Have Separately Evolved 218 Telomere Length Is Regulated by Cells and Organisms 264
Phylogenetic Trees Constructed from a Comparison of DNA Summary 265
Sequences Trace the Relationships of All Organisms 219 DNA REPAIR 266
A Comparison of Human and Mouse Chromosomes Shows Without DNA Repair, Spontaneous DNA Damage Would Rapidly
DNA repair

How the Structures of Genomes Diverge 221 Change DNA Sequences 267
The Size of a Vertebrate Genome Reflects the Relative Rates The DNA Double Helix Is Readily Repaired 268
of DNA Addition and DNA Loss in a Lineage 222 DNA Damage Can Be Removed by More Than One Pathway 269
We Can Infer the Sequence of Some Ancient Genomes 223 Coupling Nucleotide Excision Repair to Transcription Ensures
Multispecies Sequence Comparisons Identify Conserved DNA That the Cell’s Most Important DNA Is Efficiently Repaired 271
Sequences of Unknown Function 224 The Chemistry of the DNA Bases Facilitates Damage Detection 271
Changes in Previously Conserved Sequences Can Help Special Translesion DNA Polymerases Are Used in Emergencies 273
Decipher Critical Steps in Evolution 226 Double-Strand Breaks Are Efficiently Repaired 273
Mutations in the DNA Sequences That Control Gene Expression DNA Damage Delays Progression of the Cell Cycle 276
Have Driven Many of the Evolutionary Changes in Vertebrates 227 Summary 276
Gene Duplication Also Provides an Important Source of Genetic HOMOLOGOUS RECOMBINATION 276
Novelty During Evolution 227 Homologous Recombination Has Common Features in All Cells 277
Recombination

Duplicated Genes Diverge 228 DNA Base-Pairing Guides Homologous Recombination 277
The Evolution of the Globin Gene Family Shows How DNA Homologous Recombination Can Flawlessly Repair Double-
Duplications Contribute to the Evolution of Organisms 229 Strand Breaks in DNA 278
Genes Encoding New Proteins Can Be Created by the Strand Exchange Is Carried Out by the RecA/Rad51 Protein 279
Recombination of Exons 230 Homologous Recombination Can Rescue Broken DNA
Neutral Mutations Often Spread to Become Fixed in a Population, Replication Forks 280
with a Probability That Depends on Population Size 230 Cells Carefully Regulate the Use of Homologous Recombination
A Great Deal Can Be Learned from Analyses of the Variation in DNA Repair 280
Among Humans 232 Homologous Recombination Is Crucial for Meiosis 282
Summary 234 Meiotic Recombination Begins with a Programmed Double-Strand
Problems 234 Break 282
References 236 Holliday Junctions Are Formed During Meiosis 284
Homologous Recombination Produces Both Crossovers and
Chapter 5 DNA Replication, Repair, and Non-Crossovers During Meiosis 284
Recombination 237 Homologous Recombination Often Results in Gene Conversion 286
Summary 286
THE MAINTENANCE OF DNA SEQUENCES 237 TRANSPOSITION AND CONSERVATIVE SITE-SPECIFIC
Replication

Mutation Rates Are Extremely Low 237 RECOMBINATION 287

Low Mutation Rates Are Necessary for Life as We Know It 238 Through Transposition, Mobile Genetic Elements Can Insert
Summary 239 Into Any DNA Sequence 288
DNA REPLICATION MECHANISMS 239 DNA-Only Transposons Can Move by a Cut-and-Paste
Base-Pairing Underlies DNA Replication and DNA Repair 239 Mechanism 288
The DNA Replication Fork Is Asymmetrical 240 Some Viruses Use a Transposition Mechanism to Move
The High Fidelity of DNA Replication Requires Several Themselves Into Host-Cell Chromosomes 290
Proofreading Mechanisms 242 Retroviral-like Retrotransposons Resemble Retroviruses, but
Only DNA Replication in the 5ʹ-to-3ʹ Direction Allows Efficient Lack a Protein Coat 291
Error Correction 244 A Large Fraction of the Human Genome Is Composed of
A Special Nucleotide-Polymerizing Enzyme Synthesizes Short
Genomes Nonretroviral Retrotransposons 291
RNA Primer Molecules on the Lagging Strand 245 Different Transposable Elements Predominate in Different
Special Proteins Help to Open Up the DNA Double Helix in Front Organisms 292
of the Replication Fork 246 Genome Sequences Reveal the Approximate Times at Which
A Sliding Ring Holds a Moving DNA Polymerase Onto the DNA 246 Transposable Elements Have Moved 292
 xxiv DETAILED CONTENTS
Recombination

Conservative Site-Specific Recombination Can Reversibly Proteins Are Made on Polyribosomes 349
Rearrange DNA 292 There Are Minor Variations in the Standard Genetic Code 349
Conservative Site-Specific Recombination Can Be Used to Inhibitors of Prokaryotic Protein Synthesis Are Useful as
Turn Genes On or Off 294 Antibiotics 351
Bacterial Conservative Site-Specific Recombinases Have Become Quality Control Mechanisms Act to Prevent Translation of
Powerful Tools for Cell and Developmental Biologists 294 Damaged mRNAs 351
Summary 295 Some Proteins Begin to Fold While Still Being Synthesized 353
Problems 296 Molecular Chaperones Help Guide the Folding of Most Proteins 354
References 298 Cells Utilize Several Types of Chaperones 355
Exposed Hydrophobic Regions Provide Critical Signals for
Protein Quality Control 357
Chapter 6 How Cells Read the Genome: The Proteasome Is a Compartmentalized Protease with
From DNA to Protein 299 Sequestered Active Sites 357
From DNA to RNA 301 Many Proteins Are Controlled by Regulated Destruction 359
Transcription

RNA Molecules Are Single-Stranded 302 There Are Many Steps From DNA to Protein 361
Transcription Produces RNA Complementary to One Strand Summary 362
of DNA 302 The RNA World and the Origins of Life 362
RNA Polymerases Carry Out Transcription 303 Single-Stranded RNA Molecules Can Fold into Highly Elaborate
Cells Produce Different Categories of RNA Molecules 305 Structures 363
Signals Encoded in DNA Tell RNA Polymerase Where to Start RNA Can Both Store Information and Catalyze Chemical
and Stop 306 Reactions 364
Transcription Start and Stop Signals Are Heterogeneous in How Did Protein Synthesis Evolve? 365
Nucleotide Sequence 307 All Present-Day Cells Use DNA as Their Hereditary Material 365
Transcription Initiation in Eukaryotes Requires Many Proteins 309 Summary 366
RNA Polymerase II Requires a Set of General Transcription Problems 366
Factors 310 References 368
Polymerase II Also Requires Activator, Mediator, and Chromatin-
Modifying Proteins 312
Transcription Elongation in Eukaryotes Requires Accessory
Chapter 7 Control of Gene Expression 369
Gene Regulation

Proteins 313 An Overview of Gene Control 369

Transcription Creates Superhelical Tension 314 The Different Cell Types of a Multicellular Organism Contain
Transcription Elongation in Eukaryotes Is Tightly Coupled to RNA the Same DNA 369
Processing 315 Different Cell Types Synthesize Different Sets of RNAs and
RNA Capping Is the First Modification of Eukaryotic Pre-mRNAs 316 Proteins 370
RNA Splicing Removes Intron Sequences from Newly External Signals Can Cause a Cell to Change the Expression
Transcribed Pre-mRNAs 317 of Its Genes 372
Nucleotide Sequences Signal Where Splicing Occurs 319 Gene Expression Can Be Regulated at Many of the Steps
RNA Splicing Is Performed by the Spliceosome 319 in the Pathway from DNA to RNA to Protein 372
The Spliceosome Uses ATP Hydrolysis to Produce a Complex Summary 373
Series of RNA–RNA Rearrangements 321
Other Properties of Pre-mRNA and Its Synthesis Help to Explain CONTROL OF TRANSCRIPTION BY SEQUENCE-SPECIFIC
the Choice of Proper Splice Sites 321 DNA-BINDING PROTEINS 373
Chromatin Structure Affects RNA Splicing 323 The Sequence of Nucleotides in the DNA Double Helix Can Be
RNA Splicing Shows Remarkable Plasticity 323 Read by Proteins 373
Spliceosome-Catalyzed RNA Splicing Probably Evolved from Transcription Regulators Contain Structural Motifs That Can
Self-splicing Mechanisms 324 Read DNA Sequences 374
RNA-Processing Enzymes Generate the 3ʹ End of Eukaryotic Dimerization of Transcription Regulators Increases Their Affinity
mRNAs 324 and Specificity for DNA 375
Mature Eukaryotic mRNAs Are Selectively Exported from the Transcription Regulators Bind Cooperatively to DNA 378
Nucleus 325 Nucleosome Structure Promotes Cooperative Binding of
Noncoding RNAs Are Also Synthesized and Processed in the Transcription Regulators 379
Nucleus 327 Summary 380
The Nucleolus Is a Ribosome-Producing Factory 329 TRANSCRIPTION REGULATORS SWITCH GENES ON
The Nucleus Contains a Variety of Subnuclear Aggregates 331 AND OFF 380
Summary 333 The Tryptophan Repressor Switches Genes Off 380
From RNA to Protein 333 Repressors Turn Genes Off and Activators Turn Them On 381
Translation

An mRNA Sequence Is Decoded in Sets of Three Nucleotides 334 An Activator and a Repressor Control the Lac Operon 382
tRNA Molecules Match Amino Acids to Codons in mRNA 334 DNA Looping Can Occur During Bacterial Gene Regulation 383
tRNAs Are Covalently Modified Before They Exit from the Nucleus 336 Complex Switches Control Gene Transcription in Eukaryotes 384
Specific Enzymes Couple Each Amino Acid to Its Appropriate A Eukaryotic Gene Control Region Consists of a Promoter
tRNA Molecule 336 Plus Many cis-Regulatory Sequences 384
Editing by tRNA Synthetases Ensures Accuracy 338 Eukaryotic Transcription Regulators Work in Groups 385
Amino Acids Are Added to the C-terminal End of a Growing Activator Proteins Promote the Assembly of RNA Polymerase
Polypeptide Chain 339 at the Start Point of Transcription 386
The RNA Message Is Decoded in Ribosomes 340 Eukaryotic Transcription Activators Direct the Modification of
Elongation Factors Drive Translation Forward and Improve Its Local Chromatin Structure 386
Accuracy 343 Transcription Activators Can Promote Transcription by Releasing
Many Biological Processes Overcome the Inherent Limitations of RNA Polymerase from Promoters 388
Complementary Base-Pairing 345 Transcription Activators Work Synergistically 388
Accuracy in Translation Requires an Expenditure of Free Energy 345 Eukaryotic Transcription Repressors Can Inhibit Transcription
The Ribosome Is a Ribozyme 346 in Several Ways 389
Nucleotide Sequences in mRNA Signal Where to Start Protein Insulator DNA Sequences Prevent Eukaryotic Transcription
Synthesis 347 Regulators from Influencing Distant Genes 391
Stop Codons Mark the End of Translation 348 Summary 392
 DETAILED CONTENTS xxv

MOLECULAR GENETIC MECHANISMS THAT CREATE AND Hybridoma Cell Lines Are Factories That Produce Monoclonal
MAINTAIN SPECIALIZED CELL TYPES 392 Antibodies 444
Complex Genetic Switches That Regulate Drosophila Summary 445
Development Are Built Up from Smaller Molecules 392 PURIFYING PROTEINS 445
The Drosophila Eve Gene Is Regulated by Combinatorial Controls 394 Cells Can Be Separated into Their Component Fractions 445
Transcription Regulators Are Brought Into Play by Extracellular Cell Extracts Provide Accessible Systems to Study Cell Functions 447
Signals 395 Proteins Can Be Separated by Chromatography 448
Combinatorial Gene Control Creates Many Different Cell Types 396 Immunoprecipitation Is a Rapid Affinity Purification Method 449
Specialized Cell Types Can Be Experimentally Reprogrammed Genetically Engineered Tags Provide an Easy Way to Purify
to Become Pluripotent Stem Cells 398 Proteins 450
Combinations of Master Transcription Regulators Specify Cell Purified Cell-free Systems Are Required for the Precise
Types by Controlling the Expression of Many Genes 398 Dissection of Molecular Functions 451
Specialized Cells Must Rapidly Turn Sets of Genes On and Off 399 Summary 451
Differentiated Cells Maintain Their Identity 400
Transcription Circuits Allow the Cell to Carry Out Logic Operations 402 ANALYZING PROTEINS 452
Gene Regulation - epigenetics

Proteins Can Be Separated by SDS Polyacrylamide-Gel

Diagnostics
Summary 404
Electrophoresis 452
MECHANISMS THAT REINFORCE CELL MEMORY IN Two-Dimensional Gel Electrophoresis Provides Greater Protein
plants and animals 404 Separation 452
Patterns of DNA Methylation Can Be Inherited When Vertebrate Specific Proteins Can Be Detected by Blotting with Antibodies 454
Cells Divide 404 Hydrodynamic Measurements Reveal the Size and Shape of
CG-Rich Islands Are Associated with Many Genes in Mammals 405 a Protein Complex 455
Genomic Imprinting Is Based on DNA Methylation 407 Mass Spectrometry Provides a Highly Sensitive Method for
Chromosome-Wide Alterations in Chromatin Structure Can Be
Identifying Unknown Proteins 455
Inherited 409
Sets of Interacting Proteins Can Be Identified by Biochemical
Epigenetic Mechanisms Ensure That Stable Patterns of Gene
Methods 457
Expression Can Be Transmitted to Daughter Cells 411
Summary 413 Optical Methods Can Monitor Protein Interactions 458
Protein Function Can Be Selectively Disrupted With Small
POST-TRANSCRIPTIONAL CONTROLS 413 Molecules 459
Transcription Attenuation Causes the Premature Termination of Protein Structure Can Be Determined Using X-Ray Diffraction 460
Some RNA Molecules 414 NMR Can Be Used to Determine Protein Structure in Solution 461
Riboswitches Probably Represent Ancient Forms of Gene Control 414 Protein Sequence and Structure Provide Clues About Protein
Alternative RNA Splicing Can Produce Different Forms of a Protein Function 462
from the Same Gene 415 Summary 463
The Definition of a Gene Has Been Modified Since the Discovery
of Alternative RNA Splicing 416 ANALYZING AND MANIPULATING DNA 463
Restriction Nucleases Cut Large DNA Molecules into Specific
Recombinant DNA technology

A Change in the Site of RNA Transcript Cleavage and Poly-A

Addition Can Change the C-terminus of a Protein 417 Fragments 464
RNA Editing Can Change the Meaning of the RNA Message 418 Gel Electrophoresis Separates DNA Molecules of Different Sizes 465
RNA Transport from the Nucleus Can Be Regulated 419 Purified DNA Molecules Can Be Specifically Labeled with
Some mRNAs Are Localized to Specific Regions of the Cytosol 421 Radioisotopes or Chemical Markers in vitro 467
The 5ʹ and 3ʹ Untranslated Regions of mRNAs Control Their Genes Can Be Cloned Using Bacteria 467
Translation 422 An Entire Genome Can Be Represented in a DNA Library 469
The Phosphorylation of an Initiation Factor Regulates Protein Genomic and cDNA Libraries Have Different Advantages and
Synthesis Globally 423 Drawbacks 471
Initiation at AUG Codons Upstream of the Translation Start Can Hybridization Provides a Powerful, But Simple Way to Detect
Regulate Eukaryotic Translation Initiation 424 Specific Nucleotide Sequences 472
Internal Ribosome Entry Sites Provide Opportunities for Genes Can Be Cloned in vitro Using PCR 473
Translational Control 425 PCR Is Also Used for Diagnostic and Forensic Applications 474
Changes in mRNA Stability Can Regulate Gene Expression 426 Both DNA and RNA Can Be Rapidly Sequenced 477
Regulation of mRNA Stability Involves P-bodies and Stress To Be Useful, Genome Sequences Must Be Annotated 477
Granules 427 DNA Cloning Allows Any Protein to be Produced in Large
Summary 428 Amounts 483
REGULATION OF GENE EXPRESSION BY NONCODING RNAs 429 Summary 484
Small Noncoding RNA Transcripts Regulate Many Animal and STUDYING GENE EXPRESSION AND FUNCTION 485
Plant Genes Through RNA Interference 429
Gene Regulation

Classical Genetics Begins by Disrupting a Cell Process by

miRNAs Regulate mRNA Translation and Stability 429 Random Mutagenesis 485
RNA Interference Is Also Used as a Cell Defense Mechanism 431 Genetic Screens Identify Mutants with Specific Abnormalities 488
RNA Interference Can Direct Heterochromatin Formation 432 Mutations Can Cause Loss or Gain of Protein Function 489
piRNAs Protect the Germ Line from Transposable Elements 433 Complementation Tests Reveal Whether Two Mutations Are in the
RNA Interference Has Become a Powerful Experimental Tool 433 Same Gene or Different Genes 490
Bacteria Use Small Noncoding RNAs to Protect Themselves Gene Products Can Be Ordered in Pathways by Epistasis
from Viruses 433 Analysis 490
Long Noncoding RNAs Have Diverse Functions in the Cell 435 Mutations Responsible for a Phenotype Can Be Identified
Diagnostics

Summary 436 Through DNA Analysis 491

Problems 436 Rapid and Cheap DNA Sequencing Has Revolutionized
References 438 Human Genetic Studies 491
Linked Blocks of Polymorphisms Have Been Passed Down
Chapter 8 Analyzing Cells, Molecules, and from Our Ancestors 492
Systems 439 Polymorphisms Can Aid the Search for Mutations Associated
with Disease 493
ISOLATING CELLS AND GROWING THEM IN CULTURE 440 Genomics Is Accelerating the Discovery of Rare Mutations That
Cells Can Be Isolated from Tissues 440 Predispose Us to Serious Disease 493
Cells Can Be Grown in Culture 440 Reverse Genetics Begins with a Known Gene and Determines
Eukaryotic Cell Lines Are a Widely Used Source of Which Cell Processes Require Its Function 494
Homogeneous Cells 442 Animals and Plants Can Be Genetically Altered 495
 xxvi DETAILED CONTENTS

The Bacterial CRISPR System Has Been Adapted to Edit Superresolution Fluorescence Techniques Can Overcome
Genomes in a Wide Variety of Species 497 Diffraction-Limited Resolution 549
Large Collections of Engineered Mutations Provide a Tool for Superresolution Can Also be Achieved Using Single-Molecule
Examining the Function of Every Gene in an Organism 498 Localization Methods 551
RNA Interference Is a Simple and Rapid Way to Test Gene Summary 554
Function 499 Looking at Cells and Molecules in the Electron
Reporter Genes Reveal When and Where a Gene Is Expressed 501 Microscope 554
In situ Hybridization Can Reveal the Location of mRNAs and The Electron Microscope Resolves the Fine Structure of the Cell 554
Diagnostics

Noncoding RNAs 502 Biological Specimens Require Special Preparation for Electron
Expression of Individual Genes Can Be Measured Using Microscopy 555
Quantitative RT-PCR 502 Specific Macromolecules Can Be Localized by Immunogold
Analysis of mRNAs by Microarray or RNA-seq Provides a Electron Microscopy 556
Snapshot of Gene Expression 503 Different Views of a Single Object Can Be Combined to Give
Genome-wide Chromatin Immunoprecipitation Identifies Sites a Three-Dimensional Reconstruction 557
on the Genome Occupied by Transcription Regulators 505 Images of Surfaces Can Be Obtained by Scanning Electron
Ribosome Profiling Reveals Which mRNAs Are Being Translated Microscopy 558
in the Cell 505 Negative Staining and Cryoelectron Microscopy Both Allow
Recombinant DNA Methods Have Revolutionized Human Health 506 Macromolecules to Be Viewed at High Resolution 559
Transgenic Plants Are Important for Agriculture 507 Multiple Images Can Be Combined to Increase Resolution 561
Summary 508 Summary 562
MATHEMATICAL ANALYSIS OF CELL FUNCTIONS 509 Problems 563
Regulatory Networks Depend on Molecular Interactions 509 References 564
Differential Equations Help Us Predict Transient Behavior 512
Both Promoter Activity and Protein Degradation Affect the Rate
of Change of Protein Concentration 513
Chapter 10 Membrane Structure 565
The Time Required to Reach Steady State Depends on Protein The Lipid Bilayer 566
Lifetime 514 Phosphoglycerides, Sphingolipids, and Sterols Are the Major
Quantitative Methods Are Similar for Transcription Repressors Lipids in Cell Membranes 566
and Activators 514 Phospholipids Spontaneously Form Bilayers 568
Negative Feedback Is a Powerful Strategy in Cell Regulation 515 The Lipid Bilayer Is a Two-dimensional Fluid 569
Delayed Negative Feedback Can Induce Oscillations 516 The Fluidity of a Lipid Bilayer Depends on Its Composition 571
DNA Binding By a Repressor or an Activator Can Be Cooperative 516 Despite Their Fluidity, Lipid Bilayers Can Form Domains of
Positive Feedback Is Important for Switchlike Responses Different Compositions 572
and Bistability 518 Lipid Droplets Are Surrounded by a Phospholipid Monolayer 573
Robustness Is an Important Characteristic of Biological Networks 520 The Asymmetry of the Lipid Bilayer Is Functionally Important 573
Two Transcription Regulators That Bind to the Same Gene Glycolipids Are Found on the Surface of All Eukaryotic Plasma
Promoter Can Exert Combinatorial Control 520 Membranes 575
An Incoherent Feed-forward Interaction Generates Pulses 522 Summary 576
A Coherent Feed-forward Interaction Detects Persistent Inputs 522 Membrane Proteins 576
The Same Network Can Behave Differently in Different Cells Due Membrane Proteins Can Be Associated with the Lipid Bilayer
to Stochastic Effects 523 in Various Ways 576
Several Computational Approaches Can Be Used to Model the Lipid Anchors Control the Membrane Localization of Some
Reactions in Cells 524 Signaling Proteins 577
Statistical Methods Are Critical For the Analysis of Biological Data 524 In Most Transmembrane Proteins, the Polypeptide Chain
Summary 525 Crosses the Lipid Bilayer in an α-Helical Conformation 579
Problems 525 Transmembrane α Helices Often Interact with One Another 580
References 528 Some β Barrels Form Large Channels 580
Many Membrane Proteins Are Glycosylated 582
Chapter 9 Visualizing Cells 529 Membrane Proteins Can Be Solubilized and Purified in Detergents 583
Bacteriorhodopsin Is a Light-driven Proton (H+) Pump That
Looking at Cells in the Light Microscope 529 Traverses the Lipid Bilayer as Seven α Helices 586
The Light Microscope Can Resolve Details 0.2 μm Apart 530 Membrane Proteins Often Function as Large Complexes 588
Photon Noise Creates Additional Limits to Resolution When Many Membrane Proteins Diffuse in the Plane of the Membrane 588
Light Levels Are Low 532 Cells Can Confine Proteins and Lipids to Specific Domains
Living Cells Are Seen Clearly in a Phase-Contrast or a Within a Membrane 590
Differential-Interference-Contrast Microscope 533 The Cortical Cytoskeleton Gives Membranes Mechanical
Images Can Be Enhanced and Analyzed by Digital Techniques 534 Strength and Restricts Membrane Protein Diffusion 591
Intact Tissues Are Usually Fixed and Sectioned Before Microscopy 535 Membrane-bending Proteins Deform Bilayers 593
Specific Molecules Can Be Located in Cells by Fluorescence Summary 594
Microscopy 536 Problems 595
Antibodies Can Be Used to Detect Specific Molecules 539 References 596
Imaging of Complex Three-Dimensional Objects Is Possible with
the Optical Microscope 540 Chapter 11 Membrane Transport of Small Molecules
The Confocal Microscope Produces Optical Sections by and the Electrical Properties of Membranes 597
Excluding Out-of-Focus Light 540
Individual Proteins Can Be Fluorescently Tagged in Living Cells PRINCIPLES OF MEMBRANE TRANSPORT 597
and Organisms 542 Protein-Free Lipid Bilayers Are Impermeable to Ions 598
Protein Dynamics Can Be Followed in Living Cells 543 There Are Two Main Classes of Membrane Transport Proteins:
Light-Emitting Indicators Can Measure Rapidly Changing Transporters and Channels 598
Intracellular Ion Concentrations 546 Active Transport Is Mediated by Transporters Coupled to an
Single Molecules Can Be Visualized by Total Internal Reflection Energy Source 599
Fluorescence Microscopy 547 Summary 600
Individual Molecules Can Be Touched, Imaged, and Moved Using TRANSPORTERS AND ACTIVE MEMBRANE TRANSPORT 600
Atomic Force Microscopy 548 Active Transport Can Be Driven by Ion-Concentration Gradients 601
DETAILED CONTENTS xxvii

Transporters in the Plasma Membrane Regulate Cytosolic pH 604 Nuclear Import Receptors Bind to Both Nuclear Localization
An Asymmetric Distribution of Transporters in Epithelial Cells Signals and NPC Proteins 652
Underlies the Transcellular Transport of Solutes 605 Nuclear Export Works Like Nuclear Import, But in Reverse 652
There Are Three Classes of ATP-Driven Pumps 606 The Ran GTPase Imposes Directionality on Transport Through
A P-type ATPase Pumps Ca2+ into the Sarcoplasmic Reticulum NPCs 653
in Muscle Cells 606 Transport Through NPCs Can Be Regulated by Controlling
The Plasma Membrane Na+-K+ Pump Establishes Na+ and K+ Access to the Transport Machinery 654
Gradients Across the Plasma Membrane 607 During Mitosis the Nuclear Envelope Disassembles 656
ABC Transporters Constitute the Largest Family of Membrane Summary 657
Transport Proteins 609 The Transport of Proteins into Mitochondria and
Summary 611 Chloroplasts 658
CHANNELS AND THE ELECTRICAL PROPERTIES OF Translocation into Mitochondria Depends on Signal Sequences
MEMBRANES 611 and Protein Translocators 659
Aquaporins Are Permeable to Water But Impermeable to Ions 612 Mitochondrial Precursor Proteins Are Imported as Unfolded
Ion Channels Are Ion-Selective and Fluctuate Between Open Polypeptide Chains 660
and Closed States 613 ATP Hydrolysis and a Membrane Potential Drive Protein Import
The Membrane Potential in Animal Cells Depends Mainly on K+ Into the Matrix Space 661
Leak Channels and the K+ Gradient Across the Plasma Bacteria and Mitochondria Use Similar Mechanisms to Insert
Membrane 615 Porins into their Outer Membrane 662
The Resting Potential Decays Only Slowly When the Na+-K+ Transport Into the Inner Mitochondrial Membrane and
Pump Is Stopped 615 Intermembrane Space Occurs Via Several Routes 663
The Three-Dimensional Structure of a Bacterial K+ Channel Two Signal Sequences Direct Proteins to the Thylakoid Membrane
Shows How an Ion Channel Can Work 617 in Chloroplasts 664
Mechanosensitive Channels Protect Bacterial Cells Against Summary 666
Extreme Osmotic Pressures 619
The Function of a Neuron Depends on Its Elongated Structure 620 Peroxisomes 666
Voltage-Gated Cation Channels Generate Action Potentials in Peroxisomes Use Molecular Oxygen and Hydrogen Peroxide
Electrically Excitable Cells 621 to Perform Oxidation Reactions 666
The Use of Channelrhodopsins Has Revolutionized the Study A Short Signal Sequence Directs the Import of Proteins into
of Neural Circuits 623 Peroxisomes 667
Myelination Increases the Speed and Efficiency of Action Potential Summary 669
Propagation in Nerve Cells 625 The Endoplasmic Reticulum 669
Patch-Clamp Recording Indicates That Individual Ion Channels The ER Is Structurally and Functionally Diverse 670
Open in an All-or-Nothing Fashion 626 Signal Sequences Were First Discovered in Proteins Imported
Voltage-Gated Cation Channels Are Evolutionarily and Structurally into the Rough ER 672
Related 626 A Signal-Recognition Particle (SRP) Directs the ER Signal
Different Neuron Types Display Characteristic Stable Firing Sequence to a Specific Receptor in the Rough ER Membrane 673
Properties 627 The Polypeptide Chain Passes Through an Aqueous Channel
Transmitter-Gated Ion Channels Convert Chemical Signals into in the Translocator 675
Electrical Ones at Chemical Synapses 627 Translocation Across the ER Membrane Does Not Always
Chemical Synapses Can Be Excitatory or Inhibitory 629 Require Ongoing Polypeptide Chain Elongation 677
The Acetylcholine Receptors at the Neuromuscular Junction Are In Single-Pass Transmembrane Proteins, a Single Internal ER
Excitatory Transmitter-Gated Cation Channels 630 Signal Sequence Remains in the Lipid Bilayer as a Membrane-
Neurons Contain Many Types of Transmitter-Gated Channels 631 spanning α Helix 677
Many Psychoactive Drugs Act at Synapses 631 Combinations of Start-Transfer and Stop-Transfer Signals
Neuromuscular Transmission Involves the Sequential Activation Determine the Topology of Multipass Transmembrane Proteins 679
of Five Different Sets of Ion Channels 632 ER Tail-anchored Proteins Are Integrated into the ER Membrane
Single Neurons Are Complex Computation Devices 633 by a Special Mechanism 682
Neuronal Computation Requires a Combination of at Least Three Translocated Polypeptide Chains Fold and Assemble in the
Kinds of K+ Channels 634 Lumen of the Rough ER 682
Long-Term Potentiation (LTP) in the Mammalian Hippocampus Most Proteins Synthesized in the Rough ER Are Glycosylated by
Depends on Ca2+ Entry Through NMDA-Receptor Channels 636 the Addition of a Common N-Linked Oligosaccharide 683
Summary 637 Oligosaccharides Are Used as Tags to Mark the State of Protein
Problems 638
Folding 685
References 640
Improperly Folded Proteins Are Exported from the ER and
Degraded in the Cytosol 685
Chapter 12 Intracellular Compartments and Misfolded Proteins in the ER Activate an Unfolded Protein
Protein Sorting 641 Response 686
Some Membrane Proteins Acquire a Covalently Attached
The Compartmentalization of Cells 641 Glycosylphosphatidylinositol (GPI) Anchor 688
All Eukaryotic Cells Have the Same Basic Set of Membrane- The ER Assembles Most Lipid Bilayers 689
enclosed Organelles 641 Summary 691
Evolutionary Origins May Help Explain the Topological Problems 692
Relationships of Organelles 643 References 694
Proteins Can Move Between Compartments in Different Ways 645
Signal Sequences and Sorting Receptors Direct Proteins to the
Correct Cell Address 647 Chapter 13 Intracellular Membrane Traffic 695
Most Organelles Cannot Be Constructed De Novo: They Require The Molecular Mechanisms of Membrane
Information in the Organelle Itself 648 Transport and the Maintenance of
Summary 649 Compartmental Diversity 697
The Transport of Molecules Between the There Are Various Types of Coated Vesicles 697
Nucleus and the Cytosol 649 The Assembly of a Clathrin Coat Drives Vesicle Formation 697
Nuclear Pore Complexes Perforate the Nuclear Envelope 649 Adaptor Proteins Select Cargo into Clathrin-Coated Vesicles 698
Nuclear Localization Signals Direct Nuclear Proteins to the Nucleus 650 Phosphoinositides Mark Organelles and Membrane Domains 700
xxviii DETAILED CONTENTS

Membrane-Bending Proteins Help Deform the Membrane During Secretory Vesicle Membrane Components Are Quickly Removed
Vesicle Formation 701 from the Plasma Membrane 746
Cytoplasmic Proteins Regulate the Pinching-Off and Uncoating Some Regulated Exocytosis Events Serve to Enlarge the Plasma
of Coated Vesicles 701 Membrane 748
Monomeric GTPases Control Coat Assembly 703 Polarized Cells Direct Proteins from the Trans Golgi Network
Not All Transport Vesicles Are Spherical 704 to the Appropriate Domain of the Plasma Membrane 748
Rab Proteins Guide Transport Vesicles to Their Target Membrane 705 Summary 750
Rab Cascades Can Change the Identity of an Organelle 707 Problems 750
SNAREs Mediate Membrane Fusion 708 References 752
Interacting SNAREs Need to Be Pried Apart Before They Can
Function Again 709
Summary 710
Chapter 14 Energy Conversion: Mitochondria
and Chloroplasts 753
Transport from the ER Through the Golgi
Apparatus 710 THE MITOCHONDRION 755
Proteins Leave the ER in COPII-Coated Transport Vesicles 711 The Mitochondrion Has an Outer Membrane and an Inner
Only Proteins That Are Properly Folded and Assembled Can Membrane 757
Leave the ER 712 The Inner Membrane Cristae Contain the Machinery for Electron
Vesicular Tubular Clusters Mediate Transport from the ER to Transport and ATP Synthesis 758
the Golgi Apparatus 712 The Citric Acid Cycle in the Matrix Produces NADH 758
The Retrieval Pathway to the ER Uses Sorting Signals 713 Mitochondria Have Many Essential Roles in Cellular Metabolism 759
Many Proteins Are Selectively Retained in the Compartments A Chemiosmotic Process Couples Oxidation Energy to ATP
in Which They Function 714 Production 761
The Golgi Apparatus Consists of an Ordered Series of The Energy Derived from Oxidation Is Stored as an
Compartments 715 Electrochemical Gradient 762
Oligosaccharide Chains Are Processed in the Golgi Apparatus 716 Summary 763
Proteoglycans Are Assembled in the Golgi Apparatus 718 THE PROTON PUMPS OF THE ELECTRON-TRANSPORT
What Is the Purpose of Glycosylation? 719 CHAIN 763
Transport Through the Golgi Apparatus May Occur by The Redox Potential Is a Measure of Electron Affinities 763
Cisternal Maturation 720 Electron Transfers Release Large Amounts of Energy 764
Golgi Matrix Proteins Help Organize the Stack 721 Transition Metal Ions and Quinones Accept and Release
Summary 722 Electrons Readily 764
Transport from the Trans Golgi Network to NADH Transfers Its Electrons to Oxygen Through Three
Lysosomes 722 Large Enzyme Complexes Embedded in the Inner
Lysosomes Are the Principal Sites of Intracellular Digestion 722 Membrane 766
Lysosomes Are Heterogeneous 723 The NADH Dehydrogenase Complex Contains Separate
Plant and Fungal Vacuoles Are Remarkably Versatile Lysosomes 724 Modules for Electron Transport and Proton Pumping 768
Multiple Pathways Deliver Materials to Lysosomes 725 Cytochrome c Reductase Takes Up and Releases Protons on
Autophagy Degrades Unwanted Proteins and Organelles 726 the Opposite Side of the Crista Membrane, Thereby
A Mannose 6-Phosphate Receptor Sorts Lysosomal Hydrolases Pumping Protons 768
in the Trans Golgi Network 727 The Cytochrome c Oxidase Complex Pumps Protons and
Defects in the GlcNAc Phosphotransferase Cause a Lysosomal Reduces O2 Using a Catalytic Iron–Copper Center 770
Storage Disease in Humans 728 The Respiratory Chain Forms a Supercomplex in the Crista
Some Lysosomes and Multivesicular Bodies Undergo Membrane 772
Exocytosis 729 Protons Can Move Rapidly Through Proteins Along Predefined
Summary 729 Pathways 773
Transport into the Cell from the Plasma Summary 774
Membrane: Endocytosis 730 ATP PRODUCTION IN MITOCHONDRIA 774
Pinocytic Vesicles Form from Coated Pits in the Plasma The Large Negative Value of ∆G for ATP Hydrolysis Makes
Membrane 731 ATP Useful to the Cell 774
Not All Pinocytic Vesicles Are Clathrin-Coated 731 The ATP Synthase Is a Nanomachine that Produces ATP by
Cells Use Receptor-Mediated Endocytosis to Import Selected Rotary Catalysis 776
Extracellular Macromolecules 732 Proton-driven Turbines Are of Ancient Origin 777
Specific Proteins Are Retrieved from Early Endosomes and Mitochondrial Cristae Help to Make ATP Synthesis Efficient 778
Returned to the Plasma Membrane 734 Special Transport Proteins Exchange ATP and ADP Through
Plasma Membrane Signaling Receptors are Down-Regulated the Inner Membrane 779
by Degradation in Lysosomes 735 Chemiosmotic Mechanisms First Arose in Bacteria 780
Early Endosomes Mature into Late Endosomes 735 Summary 782
ESCRT Protein Complexes Mediate the Formation of CHLOROPLASTS AND PHOTOSYNTHESIS 782
Intralumenal Vesicles in Multivesicular Bodies 736 Chloroplasts Resemble Mitochondria But Have a Separate
Recycling Endosomes Regulate Plasma Membrane Composition 737 Thylakoid Compartment 782
Specialized Phagocytic Cells Can Ingest Large Particles 738 Chloroplasts Capture Energy from Sunlight and Use It to Fix
Summary 740 Carbon 783
Transport from the Trans Golgi Network to Carbon Fixation Uses ATP and NADPH to Convert CO2 into
the Cell Exterior: Exocytosis 741 Sugars 784
Many Proteins and Lipids Are Carried Automatically from the Sugars Generated by Carbon Fixation Can Be Stored as
Trans Golgi Network (TGN) to the Cell Surface 741 Starch or Consumed to Produce ATP 785
Secretory Vesicles Bud from the Trans Golgi Network 742 The Thylakoid Membranes of Chloroplasts Contain the Protein
Precursors of Secretory Proteins Are Proteolytically Processed Complexes Required for Photosynthesis and ATP Generation 786
During the Formation of Secretory Vesicles 743 Chlorophyll–Protein Complexes Can Transfer Either Excitation
Secretory Vesicles Wait Near the Plasma Membrane Until Energy or Electrons 787
Signaled to Release Their Contents 744 A Photosystem Consists of an Antenna Complex and a Reaction
For Rapid Exocytosis, Synaptic Vesicles Are Primed at the Center 788
Presynaptic Plasma Membrane 744 The Thylakoid Membrane Contains Two Different Photosystems
Synaptic Vesicles Can Form Directly from Endocytic Vesicles 746 Working in Series 789
 DETAILED CONTENTS xxix

Photosystem II Uses a Manganese Cluster to Withdraw Some G Proteins Signal Via Phospholipids 836
Electrons From Water 790 Ca2+ Functions as a Ubiquitous Intracellular Mediator 838
The Cytochrome b6-f Complex Connects Photosystem II to Feedback Generates Ca2+ Waves and Oscillations 838
Photosystem I 791 Ca2+/Calmodulin-Dependent Protein Kinases Mediate
Photosystem I Carries Out the Second Charge-Separation Many Responses to Ca2+ Signals 840
Step in the Z Scheme 792 Some G Proteins Directly Regulate Ion Channels 843
The Chloroplast ATP Synthase Uses the Proton Gradient Smell and Vision Depend on GPCRs That Regulate Ion Channels 843
Generated by the Photosynthetic Light Reactions to Nitric Oxide Is a Gaseous Signaling Mediator That Passes
Produce ATP 793 Between Cells 846
All Photosynthetic Reaction Centers Have Evolved From Second Messengers and Enzymatic Cascades Amplify Signals 848
a Common Ancestor 793 GPCR Desensitization Depends on Receptor Phosphorylation 848
The Proton-Motive Force for ATP Production in Mitochondria Summary 849
and Chloroplasts Is Essentially the Same 794 SIGNALING THROUGH ENZYME-COUPLED RECEPTORS 850
Chemiosmotic Mechanisms Evolved in Stages 794 Activated Receptor Tyrosine Kinases (RTKs) Phosphorylate
By Providing an Inexhaustible Source of Reducing Power, Themselves 850
Photosynthetic Bacteria Overcame a Major Evolutionary Phosphorylated Tyrosines on RTKs Serve as Docking Sites for
Obstacle 796 Intracellular Signaling Proteins 852
The Photosynthetic Electron-Transport Chains of Cyanobacteria Proteins with SH2 Domains Bind to Phosphorylated Tyrosines 852
Produced Atmospheric Oxygen and Permitted New The GTPase Ras Mediates Signaling by Most RTKs 854
Life-Forms 796 Ras Activates a MAP Kinase Signaling Module 855
Summary 798 Scaffold Proteins Help Prevent Cross-talk Between Parallel
THE GENETIC SYSTEMS OF MITOCHONDRIA AND MAP Kinase Modules 857
CHLOROPLASTS 800 Rho Family GTPases Functionally Couple Cell-Surface Receptors
The Genetic Systems of Mitochondria and Chloroplasts Resemble to the Cytoskeleton 858
Those of Prokaryotes 800 PI 3-Kinase Produces Lipid Docking Sites in the Plasma
Over Time, Mitochondria and Chloroplasts Have Exported Most Membrane 859
of Their Genes to the Nucleus by Gene Transfer 801 The PI-3-Kinase­–Akt Signaling Pathway Stimulates Animal
The Fission and Fusion of Mitochondria Are Topologically Cells to Survive and Grow 860
Complex Processes 802 RTKs and GPCRs Activate Overlapping Signaling Pathways 861
Animal Mitochondria Contain the Simplest Genetic Systems Some Enzyme-Coupled Receptors Associate with Cytoplasmic
Known 803 Tyrosine Kinases 862
Mitochondria Have a Relaxed Codon Usage and Can Have a Cytokine Receptors Activate the JAK–STAT Signaling Pathway 863
Variant Genetic Code 804 Protein Tyrosine Phosphatases Reverse Tyrosine Phosphorylations 864
Chloroplasts and Bacteria Share Many Striking Similarities 806 Signal Proteins of the TGFβ Superfamily Act Through Receptor
Organelle Genes Are Maternally Inherited in Animals and Plants 807 Serine/Threonine Kinases and Smads 865
Mutations in Mitochondrial DNA Can Cause Severe Inherited Summary 866
Diseases 807 ALTERNATIVE SIGNALING ROUTES IN GENE REGULATION 867
The Accumulation of Mitochondrial DNA Mutations Is a The Receptor Notch Is a Latent Transcription Regulatory Protein 867
Contributor to Aging 808 Wnt Proteins Bind to Frizzled Receptors and Inhibit the
Why Do Mitochondria and Chloroplasts Maintain a Costly Degradation of β-Catenin 868
Separate System for DNA Transcription and Translation? 808 Hedgehog Proteins Bind to Patched, Relieving Its Inhibition of
Summary 809 Smoothened 871
Problems 809 Many Stressful and Inflammatory Stimuli Act Through an
References 811
Gene Regulation NFκB-Dependent Signaling Pathway 873
Nuclear Receptors Are Ligand-Modulated Transcription
Chapter 15 Cell Signaling 813 Regulators 874
Circadian Clocks Contain Negative Feedback Loops That
PRINCIPLES OF CELL SIGNALING 813 Control Gene Expression 876
Extracellular Signals Can Act Over Short or Long Distances 814 Three Proteins in a Test Tube Can Reconstitute a Cyanobacterial
Extracellular Signal Molecules Bind to Specific Receptors 815 Circadian Clock 878
Gene Regulation

Each Cell Is Programmed to Respond to Specific Combinations Summary 879

of Extracellular Signals 816 SIGNALING IN PLANTS 880
There Are Three Major Classes of Cell-Surface Receptor Proteins 818 Multicellularity and Cell Communication Evolved Independently
Cell-Surface Receptors Relay Signals Via Intracellular Signaling in Plants and Animals 880
Molecules 819 Receptor Serine/Threonine Kinases Are the Largest Class of
Intracellular Signals Must Be Specific and Precise in a Noisy Cell-Surface Receptors in Plants 881
Cytoplasm 820 Ethylene Blocks the Degradation of Specific Transcription
Intracellular Signaling Complexes Form at Activated Receptors 822 Regulatory Proteins in the Nucleus 881
Modular Interaction Domains Mediate Interactions Between Regulated Positioning of Auxin Transporters Patterns Plant
Intracellular Signaling Proteins 822 Growth 882
The Relationship Between Signal and Response Varies in Different Phytochromes Detect Red Light, and Cryptochromes Detect
Signaling Pathways 824 Blue Light 883
The Speed of a Response Depends on the Turnover of Signaling Summary 885
Molecules 825 Problems 886
Cells Can Respond Abruptly to a Gradually Increasing Signal 827 References 887
Positive Feedback Can Generate an All-or-None Response 828
Negative Feedback is a Common Motif in Signaling Systems 829
Cells Can Adjust Their Sensitivity to a Signal 830 Chapter 16 The Cytoskeleton 889
Summary 831 FUNCTION AND ORIGIN OF THE CYTOSKELETON 889
SIGNALING THROUGH G-PROTEIN-COUPLED RECEPTORS 832 Cytoskeletal Filaments Adapt to Form Dynamic or Stable
Trimeric G Proteins Relay Signals From GPCRs 832 Structures 890
Some G Proteins Regulate the Production of Cyclic AMP 833 The Cytoskeleton Determines Cellular Organization and Polarity 892
Cyclic-AMP-Dependent Protein Kinase (PKA) Mediates Most Filaments Assemble from Protein Subunits That Impart Specific
of the Effects of Cyclic AMP 834 Physical and Dynamic Properties 893
xxx DETAILED CONTENTS

Accessory Proteins and Motors Regulate Cytoskeletal Filaments 894 Cell Polarization Is Controlled by Members of the Rho Protein
Bacterial Cell Organization and Division Depend on Homologs Family 955
of Eukaryotic Cytoskeletal Proteins 896 Extracellular Signals Can Activate the Three Rho Protein Family
Summary 898 Members 958
ACTIN AND ACTIN-BINDING PROTEINS 898 External Signals Can Dictate the Direction of Cell Migration 958
Actin Subunits Assemble Head-to-Tail to Create Flexible, Polar Communication Among Cytoskeletal Elements Coordinates
Filaments 898 Whole-Cell Polarization and Locomotion 959
Nucleation Is the Rate-Limiting Step in the Formation of Actin Summary 960
Filaments 899 Problems 960
Actin Filaments Have Two Distinct Ends That Grow at Different References 962
Rates 900
ATP Hydrolysis Within Actin Filaments Leads to Treadmilling at Chapter 17 The Cell Cycle 963
Steady State 901
The Functions of Actin Filaments Are Inhibited by Both Polymer- OVERVIEW OF THE CELL CYCLE 963
stabilizing and Polymer-destabilizing Chemicals 904 The Eukaryotic Cell Cycle Usually Consists of Four Phases 964
Actin-Binding Proteins Influence Filament Dynamics and Cell-Cycle Control Is Similar in All Eukaryotes 965
Organization 904 Cell-Cycle Progression Can Be Studied in Various Ways 966
Monomer Availability Controls Actin Filament Assembly 906 Summary 967

Cell Cycle
Actin-Nucleating Factors Accelerate Polymerization and THE CELL-CYCLE CONTROL SYSTEM 967
Generate Branched or Straight Filaments 906 The Cell-Cycle Control System Triggers the Major Events of
Actin-Filament-Binding Proteins Alter Filament Dynamics 907 the Cell Cycle 967
Severing Proteins Regulate Actin Filament Depolymerization 909 The Cell-Cycle Control System Depends on Cyclically Activated
Higher-Order Actin Filament Arrays Influence Cellular Cyclin-Dependent Protein Kinases (Cdks) 968
Mechanical Properties and Signaling 911 Cdk Activity Can Be Suppressed By Inhibitory Phosphorylation
Bacteria Can Hijack the Host Actin Cytoskeleton 913 and Cdk Inhibitor Proteins (CKIs) 970
Summary 914 Regulated Proteolysis Triggers the Metaphase-to-Anaphase
MYOSIN AND ACTIN 915 Transition 970
Actin-Based Motor Proteins Are Members of the Myosin Cell-Cycle Control Also Depends on Transcriptional Regulation 971
Superfamily 915 The Cell-Cycle Control System Functions as a Network of
Myosin Generates Force by Coupling ATP Hydrolysis to Biochemical Switches 972
Conformational Changes 916 Summary 974
Sliding of Myosin II Along Actin Filaments Causes Muscles S PHASE 974
Replication

to Contract 916 S-Cdk Initiates DNA Replication Once Per Cycle 974
A Sudden Rise in Cytosolic Ca2+ Concentration Initiates Chromosome Duplication Requires Duplication of Chromatin
Muscle Contraction 920 Structure 975
Heart Muscle Is a Precisely Engineered Machine 923 Cohesins Hold Sister Chromatids Together 977
Actin and Myosin Perform a Variety of Functions in Non-Muscle Summary 977
Cells 923 MITOSIS 978
Summary 925 M-Cdk Drives Entry Into Mitosis 978
MICROTUBULES 925 Dephosphorylation Activates M-Cdk at the Onset of Mitosis 978
Microtubules Are Hollow Tubes Made of Protofilaments 926 Condensin Helps Configure Duplicated Chromosomes for
Microtubules Undergo Dynamic Instability 927 Separation 979
Microtubule Functions Are Inhibited by Both Polymer-stabilizing The Mitotic Spindle Is a Microtubule-Based Machine 982
and Polymer-destabilizing Drugs 929 Microtubule-Dependent Motor Proteins Govern Spindle
A Protein Complex Containing γ-Tubulin Nucleates Microtubules 929 Assembly and Function 983
Microtubules Emanate from the Centrosome in Animal Cells 930 Multiple Mechanisms Collaborate in the Assembly of a Bipolar
Microtubule-Binding Proteins Modulate Filament Dynamics Mitotic Spindle 984
and Organization 932 Centrosome Duplication Occurs Early in the Cell Cycle 984
Microtubule Plus-End-Binding Proteins Modulate Microtubule M-Cdk Initiates Spindle Assembly in Prophase 985
Dynamics and Attachments 932 The Completion of Spindle Assembly in Animal Cells Requires
Tubulin-Sequestering and Microtubule-Severing Proteins Nuclear-Envelope Breakdown 985
Destabilize Microtubules 935 Microtubule Instability Increases Greatly in Mitosis 986
Two Types of Motor Proteins Move Along Microtubules 936 Mitotic Chromosomes Promote Bipolar Spindle Assembly 986
Microtubules and Motors Move Organelles and Vesicles 938 Kinetochores Attach Sister Chromatids to the Spindle 987
Construction of Complex Microtubule Assemblies Requires Bi-orientation Is Achieved by Trial and Error 988
Microtubule Dynamics and Motor Proteins 940 Multiple Forces Act on Chromosomes in the Spindle 990
Motile Cilia and Flagella Are Built from Microtubules and Dyneins 941 The APC/C Triggers Sister-Chromatid Separation and the
Primary Cilia Perform Important Signaling Functions in Completion of Mitosis 992
Animal Cells 942 Unattached Chromosomes Block Sister-Chromatid Separation:
Summary 943 The Spindle Assembly Checkpoint 993
INTERMEDIATE FILAMENTS AND SEPTINS 944 Chromosomes Segregate in Anaphase A and B 994
Intermediate Filament Structure Depends on the Lateral Bundling Segregated Chromosomes Are Packaged in Daughter Nuclei
and Twisting of Coiled-Coils 945 at Telophase 995
Intermediate Filaments Impart Mechanical Stability to Animal Cells 946 Summary 995
Linker Proteins Connect Cytoskeletal Filaments and Bridge the CYTOKINESIS 996
Nuclear Envelope 948 Actin and Myosin II in the Contractile Ring Generate the Force
Septins Form Filaments That Regulate Cell Polarity 949 for Cytokinesis 996
Summary 950 Local Activation of RhoA Triggers Assembly and Contraction
CELL POLARIZATION AND MIGRATION 951 of the Contractile Ring 997
Many Cells Can Crawl Across a Solid Substratum 951 The Microtubules of the Mitotic Spindle Determine the Plane
Actin Polymerization Drives Plasma Membrane Protrusion 951 of Animal Cell Division 997
Lamellipodia Contain All of the Machinery Required for Cell Motility 953 The Phragmoplast Guides Cytokinesis in Higher Plants 1000
Myosin Contraction and Cell Adhesion Allow Cells to Pull Membrane-Enclosed Organelles Must Be Distributed to
Themselves Forward 954 Daughter Cells During Cytokinesis 1001
 DETAILED CONTENTS xxxi

Some Cells Reposition Their Spindle to Divide Asymmetrically 1001 Members of the Immunoglobulin Superfamily Mediate
Mitosis Can Occur Without Cytokinesis 1002 Ca2+-Independent Cell–Cell Adhesion 1055
The G1 Phase Is a Stable State of Cdk Inactivity 1002 Summary 1056
Summary 1004 THE EXTRACELLULAR MATRIX OF ANIMALS 1057
MEIOSIS 1004 The Extracellular Matrix Is Made and Oriented by the Cells
Meiosis Includes Two Rounds of Chromosome Segregation 1004 Within It 1057
Duplicated Homologs Pair During Meiotic Prophase 1006 Glycosaminoglycan (GAG) Chains Occupy Large Amounts of
Homolog Pairing Culminates in the Formation of a Synaptonemal Space and Form Hydrated Gels 1058
Complex 1006 Hyaluronan Acts as a Space Filler During Tissue Morphogenesis
Homolog Segregation Depends on Several Unique Features and Repair 1059
of Meiosis I 1008 Proteoglycans Are Composed of GAG Chains Covalently
Crossing-Over Is Highly Regulated 1009 Linked to a Core Protein 1059
Meiosis Frequently Goes Wrong 1010 Collagens Are the Major Proteins of the Extracellular Matrix 1061
Summary 1010 Secreted Fibril-Associated Collagens Help Organize the Fibrils 1063
CONTROL OF CELL DIVISION AND CELL GROWTH 1010 Cells Help Organize the Collagen Fibrils They Secrete by
Mitogens Stimulate Cell Division 1011 Exerting Tension on the Matrix 1064
Cells Can Enter a Specialized Nondividing State 1012 Elastin Gives Tissues Their Elasticity 1065
Mitogens Stimulate G1-Cdk and G1/S-Cdk Activities 1012 Fibronectin and Other Multidomain Glycoproteins Help
Cell Cycle

DNA Damage Blocks Cell Division: The DNA Damage Response 1014 Organize the Matrix 1066
Many Human Cells Have a Built-In Limitation on the Number Fibronectin Binds to Integrins 1067
of Times They Can Divide 1016 Tension Exerted by Cells Regulates the Assembly of
Abnormal Proliferation Signals Cause Cell-Cycle Arrest or Fibronectin Fibrils 1068
Apoptosis, Except in Cancer Cells 1016 The Basal Lamina Is a Specialized Form of Extracellular Matrix 1068
Cell Proliferation is Accompanied by Cell Growth 1016 Laminin and Type IV Collagen Are Major Components of the
Proliferating Cells Usually Coordinate Their Growth and Division 1018 Basal Lamina 1069
Summary 1018 Basal Laminae Have Diverse Functions 1070
Problems 1019 Cells Have to Be Able to Degrade Matrix, as Well as Make It 1072
References 1020 Matrix Proteoglycans and Glycoproteins Regulate the
Activities of Secreted Proteins 1073
Summary 1074
Chapter 18 Cell Death 1021
CELL–MATRIX JUNCTIONS 1074
Apoptosis Eliminates Unwanted Cells 1021
Integrins Are Transmembrane Heterodimers That Link the
Apoptosis Depends on an Intracellular Proteolytic Cascade
Extracellular Matrix to the Cytoskeleton 1075
That Is Mediated by Caspases 1022
Integrin Defects Are Responsible for Many Genetic Diseases 1076
Cell-Surface Death Receptors Activate the Extrinsic Pathway
Integrins Can Switch Between an Active and an Inactive
of Apoptosis 1024
Conformation 1077
The Intrinsic Pathway of Apoptosis Depends on Mitochondria 1025
Integrins Cluster to Form Strong Adhesions 1079
Bcl2 Proteins Regulate the Intrinsic Pathway of Apoptosis 1025
Extracellular Matrix Attachments Act Through Integrins to
IAPs Help Control Caspases 1029
Control Cell Proliferation and Survival 1079
Extracellular Survival Factors Inhibit Apoptosis in Various Ways 1029
Integrins Recruit Intracellular Signaling Proteins at Sites of
Phagocytes Remove the Apoptotic Cell 1030
Cell–Matrix Adhesion 1079
Either Excessive or Insufficient Apoptosis Can Contribute to
Cell–Matrix Adhesions Respond to Mechanical Forces 1080
Disease 1031
Summary 1081
Summary 1032
Problems 1033 THE PLANT CELL WALL 1081
References 1034 The Composition of the Cell Wall Depends on the Cell Type 1082
The Tensile Strength of the Cell Wall Allows Plant Cells to
Chapter 19 Cell Junctions and the Extracellular Develop Turgor Pressure 1083
The Primary Cell Wall Is Built from Cellulose Microfibrils
Matrix 1035 Interwoven with a Network of Pectic Polysaccharides 1083
CELL–CELL JUNCTIONS 1038 Oriented Cell Wall Deposition Controls Plant Cell Growth 1085
Cadherins Form a Diverse Family of Adhesion Molecules 1038 Microtubules Orient Cell Wall Deposition 1086
Cadherins Mediate Homophilic Adhesion 1038 Summary 1087
Cadherin-Dependent Cell–Cell Adhesion Guides the Problems 1087
Organization of Developing Tissues 1040 References 1089
Epithelial–Mesenchymal Transitions Depend on Control of
Cadherins 1042 Chapter 20 Cancer 1091
Catenins Link Classical Cadherins to the Actin Cytoskeleton 1042
Adherens Junctions Respond to Forces Generated by the Actin CANCER AS A MICROEVOLUTIONARY PROCESS 1091
Cytoskeleton 1042 Cancer Cells Bypass Normal Proliferation Controls and
Tissue Remodeling Depends on the Coordination of Actin- Colonize Other Tissues 1092
Mediated Contraction With Cell–Cell Adhesion 1043 Most Cancers Derive from a Single Abnormal Cell 1093
Desmosomes Give Epithelia Mechanical Strength 1045 Cancer Cells Contain Somatic Mutations 1094
Tight Junctions Form a Seal Between Cells and a Fence A Single Mutation Is Not Enough to Change a Normal Cell
Between Plasma Membrane Domains 1047 into a Cancer Cell 1094
Tight Junctions Contain Strands of Transmembrane Adhesion Cancers Develop Gradually from Increasingly Aberrant Cells 1095
Proteins 1047 Tumor Progression Involves Successive Rounds of Random
Scaffold Proteins Organize Junctional Protein Complexes 1049 Inherited Change Followed by Natural Selection 1096
Gap Junctions Couple Cells Both Electrically and Metabolically 1050 Human Cancer Cells Are Genetically Unstable 1097
A Gap-Junction Connexon Is Made of Six Transmembrane Cancer Cells Display an Altered Control of Growth 1098
Connexin Subunits 1051 Cancer Cells Have an Altered Sugar Metabolism 1098
In Plants, Plasmodesmata Perform Many of the Same Functions Cancer Cells Have an Abnormal Ability to Survive Stress and
as Gap Junctions 1053 DNA Damage 1099
Selectins Mediate Transient Cell–Cell Adhesions in the Human Cancer Cells Escape a Built-in Limit to Cell Proliferation 1099
Bloodstream 1054 The Tumor Microenvironment Influences Cancer Development 1100
xxxii DETAILED CONTENTS

Cancer Cells Must Survive and Proliferate in a Foreign Many Cancers May Be Treatable by Enhancing the Immune
Environment 1101 Response Against the Specific Tumor 1137
Many Properties Typically Contribute to Cancerous Growth 1103 Cancers Evolve Resistance to Therapies 1139
Summary 1103 Combination Therapies May Succeed Where Treatments with
CANCER-CRITICAL GENES: HOW THEY ARE FOUND One Drug at a Time Fail 1139
AND WHAT THEY DO 1104 We Now Have the Tools to Devise Combination Therapies
The Identification of Gain-of-Function and Loss-of-Function Tailored to the Individual Patient 1140
Cancer Mutations Has Traditionally Required Different Summary 1141
Methods 1104 Problems 1141
Retroviruses Can Act as Vectors for Oncogenes That Alter Cell References 1143
Behavior 1105
Different Searches for Oncogenes Converged on the Same Chapter 21 Development of Multicellular
Gene—Ras 1106 Organisms 1145
Genes Mutated in Cancer Can Be Made Overactive in Many
Ways 1106 OVERVIEW OF DEVELOPMENT 1147
Studies of Rare Hereditary Cancer Syndromes First Identified Conserved Mechanisms Establish the Basic Animal Body Plan 1147
Tumor Suppressor Genes 1107 The Developmental Potential of Cells Becomes Progressively
Both Genetic and Epigenetic Mechanisms Can Inactivate Restricted 1148
Tumor Suppressor Genes 1108 Cell Memory Underlies Cell Decision-Making 1148
Systematic Sequencing of Cancer Cell Genomes Has Several Model Organisms Have Been Crucial for Understanding
Transformed Our Understanding of the Disease 1109 Development 1148
Many Cancers Have an Extraordinarily Disrupted Genome 1111 Genes Involved in Cell–Cell Communication and Transcriptional
Many Mutations in Tumor Cells are Merely Passengers 1111 Control Are Especially Important for Animal Development 1149
About One Percent of the Genes in the Human Genome Are Regulatory DNA Seems Largely Responsible for the Differences
Cancer-Critical 1112 Between Animal Species 1149
Disruptions in a Handful of Key Pathways Are Common to Small Numbers of Conserved Cell–Cell Signaling Pathways
Many Cancers 1113 Coordinate Spatial Patterning 1150
Mutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cells Through Combinatorial Control and Cell Memory, Simple
to Grow 1114 Signals Can Generate Complex Patterns 1150
Mutations in the p53 Pathway Enable Cancer Cells to Survive Morphogens Are Long-Range Inductive Signals That Exert
and Proliferate Despite Stress and DNA Damage 1115 Graded Effects 1151
Genome Instability Takes Different Forms in Different Cancers 1116 Lateral Inhibition Can Generate Patterns of Different Cell Types 1151
Cancers of Specialized Tissues Use Many Different Routes to Short-Range Activation and Long-Range Inhibition Can
Target the Common Core Pathways of Cancer 1117 Generate Complex Cellular Patterns 1152
Studies Using Mice Help to Define the Functions of Cancer- Asymmetric Cell Division Can Also Generate Diversity 1153
Critical Genes 1117 Initial Patterns Are Established in Small Fields of Cells and
Cancers Become More and More Heterogeneous as They Refined by Sequential Induction as the Embryo Grows 1153
Progress 1118 Developmental Biology Provides Insights into Disease and
The Changes in Tumor Cells That Lead to Metastasis Are Tissue Maintenance 1154
Still Largely a Mystery 1119 Summary 1154
A Small Population of Cancer Stem Cells May Maintain Many Mechanisms of Pattern Formation 1155
Tumors 1120 Different Animals Use Different Mechanisms to Establish Their
The Cancer Stem-Cell Phenomenon Adds to the Difficulty Primary Axes of Polarization 1155
of Curing Cancer 1121 Studies in Drosophila Have Revealed the Genetic Control
Colorectal Cancers Evolve Slowly Via a Succession of Visible Mechanisms Underlying Development 1157
Changes 1122 Egg-Polarity Genes Encode Macromolecules Deposited in the
A Few Key Genetic Lesions Are Common to a Large Fraction Egg to Organize the Axes of the Early Drosophila Embryo 1157
of Colorectal Cancers 1123 Three Groups of Genes Control Drosophila Segmentation Along
Some Colorectal Cancers Have Defects in DNA Mismatch Repair 1124 the A-P Axis 1159
The Steps of Tumor Progression Can Often Be Correlated A Hierarchy of Gene Regulatory Interactions Subdivides the
with Specific Mutations 1125 Drosophila Embryo 1159
Summary 1126 Egg-Polarity, Gap, and Pair-Rule Genes Create a Transient
CANCER PREVENTION AND TREATMENT: PRESENT AND Pattern That Is Remembered by Segment-Polarity and
FUTURE 1127 Hox Genes 1160
Epidemiology Reveals That Many Cases of Cancer Are Hox Genes Permanently Pattern the A-P Axis 1162
Preventable 1127 Hox Proteins Give Each Segment Its Individuality 1163
Sensitive Assays Can Detect Those Cancer-Causing Agents Hox Genes Are Expressed According to Their Order in the
that Damage DNA 1127 Hox Complex 1163
Fifty Percent of Cancers Could Be Prevented by Changes Trithorax and Polycomb Group Proteins Enable the Hox
in Lifestyle 1128 Complexes to Maintain a Permanent Record of Positional
Viruses and Other Infections Contribute to a Significant Information 1164
Proportion of Human Cancers 1129 The D-V Signaling Genes Create a Gradient of the Transcription
Cancers of the Uterine Cervix Can Be Prevented by Vaccination Regulator Dorsal 1164
Against Human Papillomavirus 1131 A Hierarchy of Inductive Interactions Subdivides the Vertebrate
Infectious Agents Can Cause Cancer in a Variety of Ways 1132 Embryo 1166
The Search for Cancer Cures Is Difficult but Not Hopeless 1132 A Competition Between Secreted Signaling Proteins Patterns
Traditional Therapies Exploit the Genetic Instability and Loss the Vertebrate Embryo 1168
of Cell-Cycle Checkpoint Responses in Cancer Cells 1132 The Insect Dorsoventral Axis Corresponds to the Vertebrate
New Drugs Can Kill Cancer Cells Selectively by Targeting Ventral-Dorsal Axis 1169
Specific Mutations 1133 Hox Genes Control the Vertebrate A-P Axis 1169
PARP Inhibitors Kill Cancer Cells That Have Defects in Brca1 Some Transcription Regulators Can Activate a Program That
or Brca2 Genes 1133 Defines a Cell Type or Creates an Entire Organ 1170
Small Molecules Can Be Designed to Inhibit Specific Notch-Mediated Lateral Inhibition Refines Cellular Spacing
Oncogenic Proteins 1135 Patterns 1171
DETAILED CONTENTS xxxiii

Asymmetric Cell Divisions Make Sister Cells Different 1173 Ephrin–Eph Signaling Drives Segregation of the Different Gut
Differences in Regulatory DNA Explain Morphological Differences 1174 Cell Types 1224
Summary 1175 Notch Signaling Controls Gut Cell Diversification and Helps
Developmental Timing 1176 Maintain the Stem-Cell State 1224
Molecular Lifetimes Play a Critical Part in Developmental Timing 1176 The Epidermal Stem-Cell System Maintains a Self-Renewing
A Gene-Expression Oscillator Acts as a Clock to Control Waterproof Barrier 1225
Vertebrate Segmentation 1177 Tissue Renewal That Does Not Depend on Stem Cells: Insulin-
Intracellular Developmental Programs Can Help Determine Secreting Cells in the Pancreas and Hepatocytes in the Liver 1226
the Time-Course of a Cell’s Development 1179 Some Tissues Lack Stem Cells and Are Not Renewable 1227
Cells Rarely Count Cell Divisions to Time Their Development 1180 Summary 1227
MicroRNAs Often Regulate Developmental Transitions 1180 Fibroblasts and Their Transformations:
Hormonal Signals Coordinate the Timing of Developmental the Connective-Tissue Cell Family 1228
Transitions 1182 Fibroblasts Change Their Character in Response to Chemical
Environmental Cues Determine the Time of Flowering 1182 and Physical Signals 1228
Summary 1184 Osteoblasts Make Bone Matrix 1229
Morphogenesis 1184 Bone Is Continually Remodeled by the Cells Within It 1230
Osteoclasts Are Controlled by Signals From Osteoblasts 1232
Cell Migration Is Guided by Cues in the Cell’s Environment 1185
Summary 1232
The Distribution of Migrant Cells Depends on Survival Factors 1186
Changing Patterns of Cell Adhesion Molecules Force Cells Genesis and Regeneration of Skeletal Muscle 1232
Into New Arrangements 1187 Myoblasts Fuse to Form New Skeletal Muscle Fibers 1233
Repulsive Interactions Help Maintain Tissue Boundaries 1188 Some Myoblasts Persist as Quiescent Stem Cells in the Adult 1234
Groups of Similar Cells Can Perform Dramatic Collective Summary 1235
Rearrangements 1188 Blood Vessels, Lymphatics, and Endothelial Cells 1235
Planar Cell Polarity Helps Orient Cell Structure and Movement in Endothelial Cells Line All Blood Vessels and Lymphatics 1235
Developing Epithelia 1189 Endothelial Tip Cells Pioneer Angiogenesis 1236
Interactions Between an Epithelium and Mesenchyme Generate Tissues Requiring a Blood Supply Release VEGF 1237
Branching Tubular Structures 1190 Signals from Endothelial Cells Control Recruitment of Pericytes
An Epithelium Can Bend During Development to Form a Tube and Smooth Muscle Cells to Form the Vessel Wall 1238
or Vesicle 1192 Summary 1238
Summary 1193 A Hierarchical Stem-Cell System: Blood Cell
GROWTH 1193 Formation 1239
The Proliferation, Death, and Size of Cells Determine Organism Red Blood Cells Are All Alike; White Blood Cells Can Be
Size 1194 Grouped in Three Main Classes 1239
Animals and Organs Can Assess and Regulate Total Cell Mass 1194 The Production of Each Type of Blood Cell in the Bone Marrow
Extracellular Signals Stimulate or Inhibit Growth 1196 Is Individually Controlled 1240
Summary 1197 Bone Marrow Contains Multipotent Hematopoietic Stem Cells,
NEURAL DEVELOPMENT 1198 Able to Give Rise to All Classes of Blood Cells 1242
Neurons Are Assigned Different Characters According to the Commitment Is a Stepwise Process 1243
Time and Place of Their Birth 1199 Divisions of Committed Progenitor Cells Amplify the Number of
The Growth Cone Pilots Axons Along Specific Routes Toward Specialized Blood Cells 1243
Their Targets 1201 Stem Cells Depend on Contact Signals From Stromal Cells 1244
A Variety of Extracellular Cues Guide Axons to their Targets 1202 Factors That Regulate Hematopoiesis Can Be Analyzed in Culture 1244
The Formation of Orderly Neural Maps Depends on Neuronal Erythropoiesis Depends on the Hormone Erythropoietin 1244
Specificity 1204 Multiple CSFs Influence Neutrophil and Macrophage Production 1245
Both Dendrites and Axonal Branches From the Same Neuron The Behavior of a Hematopoietic Cell Depends Partly on Chance 1245
Regulation of Cell Survival Is as Important as Regulation of Cell
Avoid One Another 1206
Proliferation 1246
Target Tissues Release Neurotrophic Factors That Control
Summary 1247
Nerve Cell Growth and Survival 1208
Formation of Synapses Depends on Two-Way Communication Regeneration and Repair 1247
Between Neurons and Their Target Cells 1209 Planarian Worms Contain Stem Cells That Can Regenerate a
Synaptic Pruning Depends on Electrical Activity and Synaptic Whole New Body 1247
Signaling 1211 Some Vertebrates Can Regenerate Entire Organs 1248
Neurons That Fire Together Wire Together 1211 Stem Cells Can Be Used Artificially to Replace Cells That Are
Summary 1213 Diseased or Lost: Therapy for Blood and Epidermis 1249
Problems 1213 Neural Stem Cells Can Be Manipulated in Culture and Used to
References 1215 Repopulate the Central Nervous System 1250
Summary 1251
Chapter 22 Stem Cells and Tissue Renewal 1217 Cell Reprogramming and Pluripotent Stem Cells 1251
Nuclei Can Be Reprogrammed by Transplantation into Foreign
Stem Cells and Renewal in Epithelial Tissues 1217 Cytoplasm 1252
The Lining of the Small Intestine Is Continually Renewed Reprogramming of a Transplanted Nucleus Involves Drastic
Through Cell Proliferation in the Crypts 1218 Epigenetic Changes 1252
Stem Cells of the Small Intestine Lie at or Near the Base of Embryonic Stem (ES) Cells Can Generate Any Part of the Body 1253
Each Crypt 1219 A Core Set of Transcription Regulators Defines and Maintains
The Two Daughters of a Stem Cell Face a Choice 1219 the ES Cell State 1254
Wnt Signaling Maintains the Gut Stem-Cell Compartment 1220 Fibroblasts Can Be Reprogrammed to Create Induced
Stem Cells at the Crypt Base Are Multipotent, Giving Rise to Pluripotent Stem Cells (iPS Cells) 1254
the Full Range of Differentiated Intestinal Cell Types 1220 Reprogramming Involves a Massive Upheaval of the Gene
The Two Daughters of a Stem Cell Do Not Always Have to Control System 1255
Become Different 1222 An Experimental Manipulation of Factors that Modify Chromatin
Paneth Cells Create the Stem-Cell Niche 1222 Can Increase Reprogramming Efficiencies 1256
A Single Lgr5-expressing Cell in Culture Can Generate an Entire ES and iPS Cells Can Be Guided to Generate Specific Adult
Organized Crypt-Villus System 1223 Cell Types and Even Whole Organs 1256
xxxiv DETAILED CONTENTS

Cells of One Specialized Type Can Be Forced to OVERVIEW OF THE ADAPTIVE IMMUNE SYSTEM 1307
Transdifferentiate Directly Into Another 1258 B Cells Develop in the Bone Marrow, T Cells in the Thymus 1308
ES and iPS Cells Are Useful for Drug Discovery and Analysis Immunological Memory Depends On Both Clonal Expansion
of Disease 1258 and Lymphocyte Differentiation 1309
Summary 1260 Lymphocytes Continuously Recirculate Through Peripheral
Problems 1260 Lymphoid Organs 1311
References 1262 Immunological Self-Tolerance Ensures That B and T Cells
Do Not Attack Normal Host Cells and Molecules 1313
Summary 1315
Chapter 23 Pathogens and Infection 1263
B CELLS AND IMMUNOGLOBULINS 1315
INTRODUCTION TO PATHOGENS AND THE HUMAN B Cells Make Immunoglobulins (Igs) as Both Cell-Surface

Recombination and DNA repair

MICROBIOTA 1263 Antigen Receptors and Secreted Antibodies 1315
The Human Microbiota Is a Complex Ecological System That Is Mammals Make Five Classes of Igs 1316
Important for Our Development and Health 1264 Ig Light and Heavy Chains Consist of Constant and Variable
Pathogens Interact with Their Hosts in Different Ways 1264 Regions 1318
Pathogens Can Contribute to Cancer, Cardiovascular Disease, Ig Genes Are Assembled From Separate Gene Segments
and Other Chronic Illnesses 1265 During B Cell Development 1319
Pathogens Can Be Viruses, Bacteria, or Eukaryotes 1266 Antigen-Driven Somatic Hypermutation Fine-Tunes Antibody
Bacteria Are Diverse and Occupy a Remarkable Variety of Responses 1321
Ecological Niches 1267 B Cells Can Switch the Class of Ig They Make 1322
Bacterial Pathogens Carry Specialized Virulence Genes 1268 Summary 1323
Bacterial Virulence Genes Encode Effector Proteins and Secretion
T CELLS AND MHC PROTEINS 1324
Systems to Deliver Effector Proteins to Host Cells 1269
T Cell Receptors (TCRs) Are Ig‑like Heterodimers 1325
Fungal and Protozoan Parasites Have Complex Life Cycles
Activated Dendritic Cells Activate Naïve T Cells 1326
Involving Multiple Forms 1271
T Cells Recognize Foreign Peptides Bound to MHC Proteins 1326
All Aspects of Viral Propagation Depend on Host Cell Machinery 1273
MHC Proteins Are the Most Polymorphic Human Proteins
Summary 1275
Known 1330
CELL BIOLOGY OF INFECTION 1276 CD4 and CD8 Co-receptors on T Cells Bind to Invariant Parts
Pathogens Overcome Epithelial Barriers to Infect the Host 1276 of MHC Proteins 1331
Pathogens That Colonize an Epithelium Must Overcome Its Developing Thymocytes Undergo Negative and Positive Selection 1332
Protective Mechanisms 1276 Cytotoxic T Cells Induce Infected Target Cells to Kill Themselves 1333
Extracellular Pathogens Disturb Host Cells Without Entering Effector Helper T Cells Help Activate Other Cells of the Innate
Them 1277 and Adaptive Immune Systems 1335
Intracellular Pathogens Have Mechanisms for Both Entering Naïve Helper T Cells Can Differentiate Into Different Types of
and Leaving Host Cells 1278 Effector T Cells 1335
Viruses Bind to Virus Receptors at the Host Cell Surface 1279 Both T and B Cells Require Multiple Extracellular Signals For
Viruses Enter Host Cells by Membrane Fusion, Pore Formation, Activation 1336
or Membrane Disruption 1280 Many Cell-Surface Proteins Belong to the Ig Superfamily 1338
Bacteria Enter Host Cells by Phagocytosis 1281 Summary 1339
Intracellular Eukaryotic Parasites Actively Invade Host Cells 1282 Problems 1340
Some Intracellular Pathogens Escape from the Phagosome References 1342
into the Cytosol 1284
Many Pathogens Alter Membrane Traffic in the Host Cell to Glossary G:1
Survive and Replicate 1284
Viruses and Bacteria Use the Host-Cell Cytoskeleton for Index I:1
Intracellular Movement 1286
Viruses Can Take Over the Metabolism of the Host Cell 1288 Tables T:1
Pathogens Can Evolve Rapidly by Antigenic Variation 1289
Error-Prone Replication Dominates Viral Evolution 1291
Drug-Resistant Pathogens Are a Growing Problem 1291
Summary 1294
Problems 1294
References 1296

Chapter 24 The Innate and Adaptive Immune

Systems 1297
THE INNATE IMMUNE SYSTEM 1298
Epithelial Surfaces Serve as Barriers to Infection 1298
Pattern Recognition Receptors (PRRs) Recognize Conserved
Features of Pathogens 1298
There Are Multiple Classes of PRRs 1299
Activated PRRs Trigger an Inflammatory Response at Sites of
Infection 1300
Phagocytic Cells Seek, Engulf, and Destroy Pathogens 1301
Complement Activation Targets Pathogens for Phagocytosis
or Lysis 1302
Virus-Infected Cells Take Drastic Measures to Prevent Viral
Replication 1303
Natural Killer Cells Induce Virus-Infected Cells to Kill Themselves 1304
Dendritic Cells Provide the Link Between the Innate and
Adaptive Immune Systems 1305
Summary 1305