Q.

CELL DIVISION CONTROLS IN MULTICELLULAR ORGANISMS

• The eukaryotic cell cycle is divided into four phases:

G1 (the period between mitosis and the initiation of nuclear DNA replication),
S (the period of nuclear DNA replication),
G2 (the period between the completion of nuclear DNA replication and
mitosis),
M (mitosis)
• passage through the cell cycle is controlled by heterodimeric protein kinases
that comprise a catalytic subunit and a regulatory subunit.
• The catalytic subunits, the cyclin-dependent kinases (CDKs), have no kinase
activity unless they are associated with a regulatory cyclin subunit.
• Each CDK can associate with a small number of different cyclins, which
determine the substrate specificity of the complex—that is, which proteins it
phosphorylates.
• Each cyclin is only present and active during the cell cycle stage it promotes
and hence restricts the kinase activity of the CDKs to which it binds to that
cell cycle stage.
• Cyclin-CDK complexes activate or inhibit hundreds of pro teins involved in cell
cycle progression by phosphorylating them at specific regulatory sites.
• Thus proper progression through the cell cycle is governed by activation of
the ap propriate cyclin-CDK complex at the appropriate time.
• As we will see, restricting cyclin expression to the appropriate cell cycle stage
is one of the many mechanisms cells employ to regulate the activities of each
cyclin-CDK heterodimer.
• The goal of each cell division is to generate two daughter cells of identical
genetic makeup. To achieve this, cell cycle events must occur in the proper
order.
• the activity of the key proteins that promote cell cycle progression, the CDKs,
fluctuates during the cell cycle. For example, CDKs that promote S phase are
active during S phase but are inactive during mitosis. CDKs that promote
mitosis are active only during mitosis. These oscillations in CDK activity are a
fundamental aspect of eukaryotic cell cycle control.
• Oscillations are generated by positive feedback mechanisms, whereby specific
CDKs promote their own activation. These positive feedback loops are
coupled to sub sequent negative feedback mechanisms by which, indirectly or
with a built-in delay, CDKs promote their own inactivation.
• The size of an organ or organism depends mainly on its total cell mass, which
depends on both the total number of cells and the size of the cells. Cell
number, in turn, depends on the amounts of cell division and cell death.
Organ and body size are therefore determined by three fundamental
processes: cell growth, cell division, and cell death. Each is independently
regulated—both by intracellular programs and by extracellular signal
molecules that control these programs.
• The extracellular signal molecules that regulate cell size and cell number are
generally either soluble secreted proteins, proteins bound to the surface of
cells, or components of the extracellular matrix. The factors that promote
organ or organism growth can be operationally divided into three major
classes:
• 1.Mitogens, which stimulate cell division, primarily by relieving intracellular
negative controls that otherwise block progress through the cell cycle.
• 2.Growth factors, which stimulate cell growth (an increase in cell mass) by
promoting the synthesis of proteins and other macromolecules and by
inhibiting their degradation.
• 3.Survival factors, which promote cell survival by suppressing apoptosis.

Q. APOPTOSIS
• Regulated cell death is a counterintuitive, but essential, pro cess in metazoan
organisms.
• Cell-cell interactions regulate cell death in two fundamentally different ways.
First, most, if not all, cells in multicellular organisms require specific protein
hormone signals to stay alive. In the absence of such survival signals,
frequently referred to as trophic factors, cells activate a “suicide” program.
Second, in some developmental contexts, including the immune system,
other specific hormone signals induce a “murder” program that kills cells.
• A different form of cell death, necrosis, occurs when cells are subjected to
injury or excessive stresses such as heat, absence of oxygen, or infection by
pathogens.
• Necrosis creates holes in the plasma membrane, causing leakage of
intracellular contents.
• Perhaps surprisingly, one form of necrosis, termed necroptosis, is often
triggered by extracellular hormones such as tumour necrosis factor alpha
(TNFα)
• The demise of cells by programmed cell death is marked by a well-defined
sequence of morphological changes, collectively referred to as apoptosis.
• Dying cells shrink, condense, and then fragment, releasing small membrane-
bound apoptotic bodies, which are then engulfed by other cells.
• The stereotypical changes that occur during apoptosis, such as condensation
of the nucleus and phagocytosis by surrounding cells, suggested to early
scientists that this type of cell death was under the control of a strict
program. This program is critical during both embryonic and adult life to
maintain normal cell number and composition.
• The genes involved in controlling cell death encode proteins with three
distinct functions:
1.“Killer” proteins are required for a cell to begin the apoptotic process.
2. “Destruction” proteins perform functions such as digesting proteins and
DNA in a dying cell.
 3. “Engulfment” proteins are required for phagocytosis of the dying cell by
another cell.
• In contrast to apoptosis, cells that die by necrosis or necroptosis exhibit very
different morphological changes.

Q. ROLE OF MPF
• A famous example of how cyclins and Cdks work together to control cell cycle
transitions is that of maturation-promoting factor (MPF). The name dates
back to the 1970s, when researchers found that cells in M phase contained an
unknown factor that could force frog egg cells (stuck in G2 phase) to enter M
phase. This mystery molecule, called MPF, was discovered in the 1980s to be
a Cdk bound to its M cyclin partner.
• The MPF complexes add phosphate tags to several different proteins in the
nuclear envelope, resulting in its breakdown (a key event of early M phase),
and also activate targets that promote chromosome condensation and other
M phase events.
• Cyclins
• Cyclins are among the most important core cell cycle regulators.
• Cyclins are a group of related proteins, and there are four basic types found
in humans and most other eukaryotes: G1 cyclins, G1-S cyclins, S cyclins, and
M cyclins.
• As the names suggest, each cyclin is associated with a particular phase,
transition, or set of phases in the cell cycle and helps drive the events of that
phase or period.
• For instance, M cyclin promotes the events of M phase, such as nuclear
envelope breakdown and chromosome condensation
• The levels of the different cyclins vary considerably across the cell cycle, as
shown in the diagram at right.
• A typical cyclin is present at low levels for most of the cycle, but increases
strongly at the stage where it's needed. M cyclin, for example, peaks
dramatically at the transition from G2 to M phase.
• G1 cyclins are unusual in that they are needed for much of the cell cycle.
• Cyclin-dependent kinases
• In order to drive the cell cycle forward, a cyclin must activate or inactivate
many target proteins inside of the cell.
• Cyclins drive the events of the cell cycle by partnering with a family of
enzymes called the cyclin-dependent kinases (Cdks).
 • A lone Cdk is inactive, but the binding of a cyclin activates it, making it a
functional enzyme and allowing it to modify target proteins.
• Cdks are kinases, enzymes that phosphorylate (attach phosphate groups to)
specific target proteins.
• The attached phosphate group acts like a switch, making the target protein
more or less active.
• When a cyclin attaches to a Cdk, it has two important effects: it activates the
Cdk as a kinase, but it also directs the Cdk to a specific set of target proteins,
ones appropriate to the cell cycle period controlled by the cyclin.
• For instance, G1/S cyclins send Cdks to S phase targets (e.g., promoting DNA
replication), while M cyclins send Cdks to M phase targets (e.g., making the
nuclear membrane break down).

Cyclins and Cdks are very evolutionarily conserved, meaning that they are found in many
different types of species, from yeast to frogs to humans. The details of the system vary a
little: for instance, yeast has just one Cdk, while humans and other mammals have multiple
Cdks that are used at different stages of the cell cycle.