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 Dedication

This book is dedicated to Dr. David Baltimore

for his pioneer work in the N F - K B field
and leadership in several fi-ontiers of biomedical sciences.
 CONTENTS
Foreword xiii

Preface xix

1. Structural Analysis of N F - K B and IKB Proteins 1

Tom Huxfordand Gourisankar Ghosh
N F - K B Structure 4
N F - K B / D N A Complex 6
N F - K B / I K B Complex 7
N F - K B p50 Homodimer/RNA Aptamer Complex 9

2. N F - K B Signal Transduction by IKK Complexes 12

Zhi' Wei Li and Michael Karin
N F - K B , I K B , IKK and the Canonical Pathway
for N F - K B Activation 12
IKKa and Noncanonical Pathway for N F - K B Activation 15
Modification of N F - K B and Its Signaling Molecules 17
Molecules Involved in Multiple N F - K B Activation
Signaling Pathway 19

3. Receptors and Adaptors for N F - K B Signaling 26

ShaO'Cong Sun and Edward W. Harhaj
Antigen Receptors 26
Receptor-Proximal Signaling Events 26
Toll-Like Receptors 30
T N F Receptor Superfamily 32
Other Receptors Mediating N F - K B Activation 36

4. Cellular Dynamics of N F - K B Associated Proteins 41

Daliya Banerjee andRanjan Sen
Nucleocytoplasmic Shutding of IKB Proteins 41
Signal Induced Degradation of IKB Proteins AA
Shutding of IKB Kinase Components 46
Shuttling of Rel Proteins Aj

5. N F - K B in Lymphopoiesis 51
Estefania Claudioy Keith Brown and Ulrich Siebenlist
N F - K B in Early Stages of Lymphocyte Development 51
Double Negative, PreTCR^ Thymocytes 54
Double Positive Thymocytes 54
Single-Positive Thymocytes and Peripheral T Cells 56
 6. N F - K B and Immune Cell Effector Fmictions 70
Hsiou-Chi Liou, Biao Feng, Wenzhi Tian, Shuhua Cheng
and Constance Y. Hsia
Brief Overview of the Immune System 70
N F - K B and Innate Immunity 71
N F - K B in Dendritic Cells 72
N F - K B in T Cell Development and Selection 7A
N F - K B in T Cell Effector Function 75
N F - K B in B Lymphocyte Clonal Expansion
and Cell Fate Determination 77
N F - K B in the Germinal Center Immune Response 78

7. Roles of N F - K B in Autoimmunity 84
Stacey Garrett and Youhai H. Chen
Roles of N F - K B in T Cell Development 84
Roles of N F - K B in Mature Lymphocytes 85
Roles of N F - K B in Apoptosis, Proliferation and Autoimmunity 86
Roles of N F - K B in Autoimmune Encephalomyelitis and Diabetes 87

8. The Central Role of N F - K B in the Regulation of Immunity

to Infection 91
Cristina M. Tato and Christopher A. Hunter
N F - K B : An Evolutionarily Conserved System Associated
with Innate Immunity 93
Toll-Like Receptors and Innate Immunity 93
The Role of N F - K B in Resistance to Infection 94
Pathogens That Interfere with N F - K B 100

9. Molecular Basis of Oncogenesis by N F - K B :

From a Bird's Eye View to a RELevant Role in Cancer 112
Yongjun Fany Jui Dutta, Nupur Gupta and Ciline Gilinas
Constitutive Rel/NF-KB Aaivity Is a Hallmark
of Many Human Cancers 113
Molecular Basis for Oncogenesis by Rel/NF-KB 117
Functional Consequences of Rel/NF-KB-Mediated
Gene Activation in Oncogenesis 119
Other Means for N F - K B to Participate in Oncogenesis 121
Conclusions and Perspectives for Therapy 122

10. N F - K B in Human Cancers 131

Elaine J. Schattner^ Richard K Furman and Alejandro Bemal
N F - K B Controls Cellular Proliferation, Adhesion and Survival 132
Tumors in Which N F - K B Is Implicated in Pathogenesis 133
Virus-Associated Tumors 135
Inhibition of N F - K B in Cancer Treatment 136
11. N F - K B in Neurons: Behavioral and Physiologic Roles
in Nervous System Function 147
Jonathan M. Levensony Marina Pizzi andJ. David Sweatt
A Synaptic Messenger 147
Signaling Pathways That Regulate Neuronal N F - K B 149
Glutamate 150
Growth Factors 150
Calcium 150
Reactive Oxygen Species 150
Protein Kinases 150
A Model for Activation of N F - K B in Neurons 151
Synaptic Plasticity 152
Memory Formation 154
Fear Motivated Learning: An Explanation 154
Fear Potentiated Startle 155
Fear Conditioning 155
Radial Arm Maze 157

12. Inhibitors of N F - K B Activity:

Tools for Treatment of Human Ailments 162
Vinay Tergaonkar, Qiutang Li and Inder M. Verma
Inhibition of N F - K B Can Be Achieved at Multiple Points
in the Pathway 163
Biological Inhibitors 163
Synthetic Inhibitors 168
Future Directions 170

Index 179
 EDITOR
Hsiou-Chi Liou
Division of Immunology
Department of Medicine
Weill Medical College of Cornell University
New York, New York, U.S.A.
Email: [email protected]
Preface, Chapter 6

CONTRIBUTORS
Daliya Banerjee Shuhua Cheng
Department of Biology Division of Immunology
Brandeis University Department of Medicine
Waltham, Massachusetts, U.S.A Weill Medical College
Chapter 4 of Cornell University
New York, New York, U.S.A.
Alejandro Bernal Chapter 6
Division of Hematology
and Medical Oncology Estefania Claudio
Weill Medical College Laboratory of Immunoregulation
of Cornell University NL\ID
New York, New York, U.S.A. National Institutes of Health
Chapter 10 Bethesda, Maryland, U.S.A.
Chapter 5
Keith Brown
Laboratory of Immunoregulation Jui Dutta
NIAID Center for Advanced Biotechnology
National Institutes of Health and Medicine
Bethesda, Maryland, U.S.A Graduate Program in Biochemistry
Chapter 5 and Molecular Biology
University of Medicine and Dentistry
Youhai H. Chen of New Jersey
Department of Pathology Piscataway, New Jersey, U.S A.
and Laboratory Medicine Chapter 9
School of Medicine
University of Pennsylvania Yongjim Fan
Philadelphia, Pennsylvania, U.S.A. Center for Advanced Biotechnology
Email: [email protected] and Medicine
Chapter 7 University of Medicine and Dentistry
of New Jersey
Piscataway, New Jersey, U.S A.
Chapter 9
Biao Feng Nupur Gupta
Division of Immunology Center for Advanced Biotechnology
Department of Medicine and Medicine
Weill Medical College Graduate Program in Biochemistry
of Cornell University and Molecular Biology
New York, New York, U.SA University of Medicine and Dentistry
Chapter 6 of New Jersey
Piscataway, New Jersey, U.SA.
Richard R- Furman Chapter 9
Division of Hematology
and Medical Oncology Edward W. Harhaj
Weill Medical College Department of Microbiology
of Cornell University and Immunology
New York, New York, U.SA and
Chapter 10 Sylvester Comprehensive Cancer Center
University of Miami School of Medicine
Stacey Garrett Miami, Florida, U.S.A.
Department of Pathology Chapter 3
and Laboratory Medicine
School of Medicine Constance Y. Hsia
University of Pennsylvania SG Cowen & Co.
Philadelphia, Pennsylvania, U.SA New York, New York, U.SA
Chapter? Chapter 6

Cdine Gdinas Christopher A. Hunter

Center for Advanced Biotechnology Department of Pathobiology
and Medicine School of Veterinary Medicine
Department of Biochemistry University of Pennsylvania
Robert Wood Johnson Medical School Philadelphia, Pennsylvania, U.S.A
University of Medicine and Dentistry Email: [email protected]
of New Jersey Chapter 8
Piscataway, New Jersey, U . S A
Email: [email protected] Tom Huxford
Chapter 9 Department of Chemistry
and Biochemistry '
Gourisankar Ghosh University of California, San Diego
Department of Chemistry La Jolla, California, U.SA.
and Biochemistry Email: [email protected]
University of California, San Diego Chapter 1
La Jolla, California, U.SA.
Email: [email protected] Michael Karin
Chapter 1 Department of Pharmacology
School of Medicine
University of California, San Diego
La Jolla, California, U.SA.
Email: [email protected]
Chapter 2
Jonathan M. Levenson Ranjan Sen
Department of Neuroscience Laboratory of Cellular
Baylor College of Medicine and Molecular Biology
Houston, Texas, U.S.A. National Institute on Aging
and Baltimore, Maryland, U.S A
Department of Pharmacology Email: [email protected]
The Waisman Center Forewordy Chapter 4
for Human Development
University of Wisconsin Medical School Ulrich Siebenlist
Madison, Wisconsin, U.S.A. Laboratory of I mmunoregulation
Email: [email protected] NL\ID
Chapter 11 National Institutes of Health
Bethesda, Maryland, U.S.A.
Qiutang Li Email: [email protected]
Laboratory of Genetics Chapter 5
The Salk Institute for Biological Studies
La JoUa, California, U.S A. Shao-Cong Sun
Chapter 12 Department of Microbiology
and Immimology
Zhi-WeiLi Pennsylvania State University
H. Lee Moffitt Cancer Center College of Medicine
and Research Institute Hershey, Pennsylvania, U.S.A
Department of Interdisciplinary Email: [email protected]
Oncology Chapter 3
University of South Florida
Tampa, Florida, U.S.A. J. David Sweatt
Email: [email protected] Department of Neuroscience
Chapter 2 Baylor College of Medicine
Houston, Texas, U.S.A.
Marina Pizzi Email: [email protected]
Division of Pharmacology Chapter 11
and Experimental Therapeutics
Department of Biomedical Sciences Cristina M. Tato
and Biotechnologies Department of Pathobiology
School of Medicine School of Veterinary Medicine
University of Brescia University of Pennsylvania
Brescia, Italy Philadelphia, Pennsylvania, U.S.A.
Email: [email protected] Chapter 8
Chapter 11
Vinay Tergaonkar
Elaine J. Schattner Laboratory of Genetics
Department of Medicine The Salk Institute for Biological Studies
Weill Medical College La JoUa, California, U.S.A.
of Cornell University Email: [email protected]
New York, New York, U.S.A. Chapter 12
Email: [email protected]
Chapter 10
Wenzhi Tian Inder M. Verma
Division of Immunology Laboratory of Genetics
Department of Medicine The Salk Institute for Biological Studies
Weill Medical College La Jolla, California, U.S A.
of Cornell University Email: [email protected]
New York, New York, U.S.A. Chapter 12
Chapter 6
 FOREWORD

The First Few Years of NF-KB

W hen Hsiou-Chi Liou first asked me to provide a personal view of

the "early years of N F - K B research" I hesitated, in large part because
retrospection seemed to be of little value at a time when we should
be looking forward, not backward. However, after mulling over the idea for
some time, I decided to do it because the evolution of N F - K B , from the
quest to understand B cell-specific transcription of immunoglobulin (Ig) K
genes to its present industry-sized scope, is a fascinating example of biologi-
cal multi-tasking by a limited gene family. In this context, I felt that the early
development of the project may be of some interest. What follows, thus, is a
personal view of the lead-up to the identification of N F - K B and the years
immediately thereafter.
Towards the end of my Ph.D. in organic chemistry I became inter-
ested in biology and approached David Baltimore for a post-doctoral posi-
tion. In the early 80s the Baltimore lab had three major research directions:
molecular immunology, retrovirology and the biology of poliovirus. My closest
encounter with the life sciences prior to this had been graduate courses in
biophysical chemistry and biochemistry, which had not prepared me suffi-
ciently to favor one of these topics over the others. Therefore, to apply for
post-doctoral fellowships I wrote three short blurbs in each of these areas for
Davids consideration. He picked one on the control of K gene recombina-
tion by DNA methylation for fiirther elaboration into a proposal. The choice
landed me in the immunology sub-group and, when I reached M.I.T. a year
later, I started as planned with chromatin structural assays and DNA methy-
lation studies in Abelson virus transformed cell lines. One of the earliest
observations we made was that the K intron enhancer coincided with a
DNase 1 hypersensitive site in cell lines that actively recombine Ig K genes.
The altered chromatin structure reflected in the hypersensitive site, with the
underlying sequence of the enhancer as its apparent cause, piqued my inter-
est as a chemist. Thus, I initiated studies to "reproduce enhancer fimction in
vitro." David, a biochemist at heart, was enthusiastically supportive.
Phil Sharp's laboratory was next door to ours. Phil, also a Ph.D. in
chemistry, was enthusiastic about another chemist s conversion to molecular
biology and lent me his copy oi Bacteria and Their Viruses as a rite of initia-
tion. He put me in touch with Andy Fire when I spoke to him about study-
ing enhancer-dependent transcription in vitro. With Andys expertise and
cooperation, we developed the first in vitro transcription extracts from B
lymphocyte cell lines and used them to study the Vk promoter and the K
enhancer. Though the effects of promoter sequences were evident in
transcription assays, we did not observe K enhancer-dependent eleva-
tion of transcription in vitro. Months of disappointing results provided the
time and the incentive to think, and rethink, the strategy. While these early
studies were in progress I had spoken to the two people at M.I.T who had
experience with enhancers. Alex Varshavsky was the first to describe that the
SV40 enhancer was located in a nucleosome-free region of the
mini-chromosome, and Alex Rich had ideas about enhancers and Z-DNA.
We even used anti-Z-DNA antibodies obtained firom Rich in some experi-
ments. These conversations forcefully emphasized how litde was known about
these regulatory sequences and indicated that going for a functional readout
in vitro may have been somewhat premature. In retrospect, good examples
of promoter/enhancer communication over significant distances remain elu-
sive to this day. Therefore, we decided to step back from the fimctional
approach and began to "simply look" for components of the enhancer.
The electrophoretic mobility shift assay (EMSA) had been developed
to study the interactions of purified bacterial DNA binding proteins with
their cognate sites. This was very different from the objective we had in
mind, which was to identify new DNA binding proteins; however, its in-
trinsic simplicity strongly recommended it as a method to work with. As a
source of putative enhancer binding proteins I setded on a new transcrip-
tion-competent nuclear extract procedure that had recently been developed
in Bob Roeder s laboratory, and set about putting the two together using
immunoglobulin-related regulatory sequences as targets. Shortly into this
new line of experimentation I was joined by Harinder Singh, then newly
arrived in Phil Sharps laboratory.
Together we made two modifications that proved to be invaluable in
making EMSA a widely-used technique in the eukaryotic gene regulation
community. First, the use of small, functionally inactive fragments of en-
hancer DNA allowed greater sensitivity and significandy increased the sig-
nal-to-noise ratio in binding gels. Though at the time it was difficult to
decide whether a functionally intact enhancer sequence was essential to re-
cruit the necessary proteins to DNA, the advant^es noted above encour-
aged us to continue with small fragments. Indeed, studies with the origin
recognition complex since then have shown that intact sequences are some-
times necessary for DNA binding. Second, the use of synthetic nucleic acid
polymers with low sequence complexity also increased the sensitivity of the
assay. Finally, with additional modifications to co-opt existing DNase 1
footprinting and methylation interference assays for use with EMSA, we
generated the first data sets using Vk promoter, K enhancer and m heavy
chain gene enhancer sequences. Amongst the proteins identified in this screen
were octamer binding proteins which have since been shown to be impor-
tant for stem cell biology, immunoglobulin expression and cell-cycle regu-
lated genes, basic helix-loop-helix (bHLH) proteins that play important roles
in lymphocyte development, leucine zipper-containing bHLH proteins that
are related to c-myc and N F - K B .
 N F - K B was identified as a mobility shifted band using the k3 frag-
ment of the K intron enhancer, and interference assays revealed an 11 base
pair binding site towards one end of the fragment; we referred to it as the KB
site. The first version of our manuscript continued to refer to the protein(s)
that generated the EMSA complex as k3 binding protein(s). Upon reading
that draft David suggested we give it a more user-friendly name, which led
us to call the protein(s) N F - K B (for nuclear factor that binds the KB site).
Unlike all other proteins identified in the initial screen, N F - K B D N A bind-
ing activity was detected only in extracts from cells that expressed immuno-
globulin light chain genes, including mature B cell lines of human and mu-
rine origin as well as plasmacytomas, but not pre-B cell lines that did not
express Ig K or X. The close correspondence between DNA binding and
light chain gene expression suggested that N F - K B was an important K gene
regulatory factor.
To fiirther strengthen the idea, we used the pre-B cell line, 70Z, that
had been shown to activate K gene transcription in response to lipopolysac-
charide (LPS) or phorbol esters (PMA). Moreover, K transcription in re-
sponse to these agents occurred in the absence of new protein synthesis,
providing an especially stringent constraint to test the validity of the hy-
pothesis. We showed that N F - K B induction by these agents indeed occurred
in the presence of translation inhibitors cycloheximide and anisomycin. These
crucial experiments substantiated the link of N F - K B expression to K gene
transcription and provided the first evidence for a post-translational mecha-
nism of N F - K B activation. Soon thereafter Mike Lenardo and Jackie Pierce
mutated the KB site of the K enhancer and showed that it was essential for
enhancer activity.
N F - K B as an important K enhancer activating protein may have been
the end of the story, but for two other observations. First, control cells treated
with translation inhibitors in the absence of LPS, or PMA, showed low but
consistent activation of N F - K B DNA binding. This led us to postulate the
existence of a "short-lived inhibitor" that suppressed N F - K B DNA binding
in unactivated cells. Second, the induction of N F - K B in pre-B cells by a
general activator such as PMA prompted us to question whether N F - K B
activation and fiinction might extend to cell types that had no connection to
immunoglobulin expression. In the original studies we found that N F - K B
DNA binding was induced in HeLa (epithelial) cells and Jurkat (T lympho-
cyte) cells by PMA in the absence of protein synthesis. These observations
provided the first glimpse that N F - K B may be more than a B lineage-specific
K gene activating protein. Identification of additional tissue-unrestricted
N F - K B activating signals soon followed, the earliest ones being
double-stranded RNA, T N F a and serum.
A series of biochemical analyses, primarily in David Baltimore's labo-
ratory, fleshed out the characters implicated from this early work. Patrick
Baeuerle showed that the nonDNA-binding form of N F - K B resided in the
cell cytosol and could be converted to the DNA binding form in elegant
experiments that used a combination of strong anionic detergent followed
by its removal in a mixed micelle. The inhibitory activity, which was bio-
chemically separable from N F - K B , was called IKB, and ultimately proved to
be the predicted "short-lived inhibitor." Baeuerle and Baltimore also showed
that N F - K B is a heterodimer composed of 50 and 65 kD subunits, of which
the latter was essential for iKB-mediated inhibition. The detergent release
assay gready aided subsequent purification of N F - K B , first by allowing a
simple scan of a variety of nonlymphoid tissue for the most abundant source
of N F - K B , and also by providing the means to reveal DNA binding activity
for capture on a sequence-specific DNA affinity matrix.
Sankar Ghosh used this strategy to purify N F - K B from rabbit lung
extracts. Peptide sequencing and molecular cloning of the 50 kD compo-
nent revealed the relationship of N F - K B to the avian oncogene v-rek as well
as the need for proteolytic processing to convert the precursor pi05 to a
DNA binding form. Sankar's purification scheme also yielded p65 and iKBa
polypeptides, the former of which was cloned by Gary Nolan to reveal an-
other v-rel homologous gene. The NF-KB/f-r^/ connection, manifest in a
300 amino acid DNA binding Rel homology domain (RHD), brought those
working on v-rel, and its cellular counterpart c-Rel^ into the rapidly expand-
ing N F - K B community. One of the early positive outcomes of this fiision
was the identification of v-Rel-associated pp40 protein as the ortholog of
iKBa purified from rabbit lung. While these studies were ongoing in the
Baltimore lab, Alain Israel and colleagues independently cloned pi05 in
their search for DNA binding proteins that regulated MHC Class I and b2
microglobulin genes. In parallel, a human cDNA encoding iKBa was iso-
lated by Steve Haskill and Al Baldwin.
As requested by the editor, I have highlighted only the earliest years of
N F - K B research here. Obviously, much has happened since then as exempli-
fied by the contributions to this book. Some highlights include the identifi-
cation of two new Rel family members, the IKB kinases and unique signal-
ing pathways to N F - K B downstream of various cell surface receptors. Addi-
tionally, the phenotypes of genetic deletions of N F - K B and NF-KB-associated
molecules have revealed the biological scope of this family of proteins. More
than 16,000 publications attest to a role for N F - K B in virtually all cell types
and all vertebrate species examined to date, with contributions to early em-
bryogenesis, defense against pathogens and the regulation of cell viability.
The fixnction of the K enhancer N F - K B binding site, however, remains enig-
matic since the demonstration by Yang Xu and colleagues that its mutation
in the endogenous locus does not affect K gene recombination or expression.
Amongst the variety of phenomena that are modulated by N F - K B , its role in
inflammatory processes has attracted the greatest attention. Both as a factor
that regulates expression of pro-inflammatory cytokines and a factor that is
activated by pro-inflammatory cytokines, N F - K B is a hot target of the phar-
maceutical industry Ironically, the very ubiquitousness of N F - K B that at-
tracted its vast following may also complicate its use as a therapeutic by
increasing the likelihood of nonspecific effects. The objective for the future
will be to find, or better still, to design, small molecule regulators that maxi-
mize positive effects while minimizing the negative.
Ranjan Sen, Ph.D.
Laboratory of Cellular and Molecular Biology
National Institute on Aging
Baltimore, Maryland, U.S.A.
 PREFACE

S
ince its discovery by Ranjan Sen and David Baltimore in the late 80s,
N F - K B has drawn the attention of experimental biologists, medical
professionals, and the biotech/pharmaceutical industry for its broad
and diverse role in all aspects of human biology and disease. Inspired by the
wealth of knowledge in this field, I have had the privilege of editing this
book so that I could share some of these recent and exciting findings.
This book is meant to provide the most current information gathered
on the N F - K B transcription factor family. Written by experts of the subject,
the book covers such topics as the structural basis and molecular mechanism
of N F - K B signal transduction, transcriptional regulation, and target gene
expression. Multiple roles for N F - K B are also explored for a growing
number of N F - K B dependent biological and pathological processes. In
particular, the ftinction of N F - K B in modulating the immune response to
pathogenic infection, as well as its involvement in autoimmunity, cancer,
and neuronal development, are each emphasized in different chapters.
Current strategies to intervene in the N F - K B signaling pathway are fiirther
discussed as a potential means of therapy.
Although the book covers many aspects of N F - K B biology, one can
anticipate that new functional roles for N F - K B in other biological or
medical disciplines will continue to emerge with the increasing availability
of new reagents, disease models, and technology. The role of N F - K B in muscle
physiology, ischemia, neuronal degenerative diseases, or cardiovascular
disease, for instance, remain uncharted areas that warrant investigation based
upon a growing body of evidence implicating N F - K B activity in these processes.
Certainly the ability to manipulate N F - K B through inactivation, deletion,
regulated expression, or gain-of-function mutation, may extend current
research beyond inflammation, autoimmunity, and tumorigenesis into novel
applications for vaccine development, tumor immunotherapy, and the
control of infectious disease.
Finally, I would like to express my appreciation for the significant
contribution from each of the authors on the N F - K B field and the book.

HsioU'Chi Liouy Ph.D.

CHAPTER 1

Structural Analysis of N F - K B
and IKB Proteins
Tom Huxford* and Gourisankar Ghosh

Abstract

B y binding specifically to DNA sequences found within their enhancer elements,

transcription factors of the N F - K B family activate the expression of genes involved
in cellular immunity, inflammation, development, and apoptosis. The maintenance of
proper cellular function requires the tight control of N F - K B levels. Regulation of N F - K B is
accomplished primarily through its association with members of the IKB family of transcrip-
tion factor inhibitor proteins. Structural characterization of various N F - K B dimers in complex
with target site DNA, IKB inhibitor proteins, and an in vitro selected RNA aptamer reveals
how conformational rearrangements of the versatile N F - K B molecule accommodate high af-
finity binding to different partners. The relative mobility of three structural and functional
units permits large conformational changes in N F - K B without changing the DNA binding
surfaces. The structures of N F - K B boimd to iKBa and IKBP further illustrate how some of the
disordered elements of these proteins become ordered and participate in the formation of these
complexes.
Introduction
The N F - K B transcription faaor system is notable for the vast array of diverse stimuli that
induce its activity, the rapidity with which it converts from an inactive to active state, and the
numerous genes whose transcription is directly influenced by N F - K B activity. ' Though
originally discovered and characterized as a nuclear factor with binding specificity toward an
element within the immunoglobulin kappa light chain gene enhancer of B lymphocytes,
transcription factors of the N F - K B family are now recognized as being present in virtually all
resting cell types as stable cytoplasmic complexes with a member of the IKB family of inhibitor
proteins.

NF'KB Activation Pathway

Inflammatory cytokines (TNF-a, interleukin-1), growth factors and hormones (EGF, insu-
lin), bacterial products (Upopolysaccharide, lipoteichoic acid), viruses (HIV-1, HTLV-1), and
their products (double-stranded RNA, Tax protein) initiate signal transduction pathways that
converge upon the multisubunit IKB kinase complex (IKK).^ IKK phosphorylates IKB associ-
ated in complex with inactive N F - K B . This leads to the rapid ubiquitinylation and degradation
of complex-associated IKB via the 26 S proteasome.^ Removal of IKB potentiates N F - K B nuclear
translocation by unmasking the type I nuclear localization signal (NLS) present within every

*Corresponding Author: Tom Huxford—Department of Chemistry and Biochemistry, University

of California, San Diego, La Jolla, California, U.S.A. Email: [email protected]

NF-KB/Rel Transcription Factor Familyy edited by Hsiou-Chi Liou.

©2006 Landes Bioscience and Springer Science+Business Media.