| Current
Medicinal Chemistry
ISSN: 0929-8673
OPEN ACCESS ARTICLES
Contents
Killing Time for Cancer Stem Cells (CSC): Discovery
and Development of Selective CSC Inhibitors,
2006, 13, 1719-1725
María Pérez-Caro and Isidro Sánchez-García
[Abstract] [Full
text article]
The Role of the MAGUK Protein CASK in Neural
Development and Synaptic Function, 2006,
13, 1915-1927
Yi-Ping Hsueh
[Abstract] [Full
text article]
Review Camptothecin: Current Perspectives,
2006, 13, 2021-2039
Qing-Yong Li, Yuan-Gang Zu, Rong-Zhen Shi and Li-Ping
Yao
[Abstract] [Full
text article]
Current Progress in Non-Invasive Imaging of Beta
Cell Mass of the Endocrine Pancreas, 2006,
13, 2761-2773
Fabiola Souza, Matthew Freeby, Kristi Hultman, Norman
Simpson, Alan Herron,Piotr Witkowsky, Eric Liu, Antonella
Maffei and Paul E. Harris
[Abstract] [Full
text article]
Anti-Galectin Compounds as Potential Anti-Cancer
Drugs, 2006, 13, 3513-3527
Laurent Ingrassia, Isabelle Camby, Florence Lefranc, Véronique
Mathieu, Prosper Nshimyumukiza, Francis Darro and Robert Kiss
[Abstract] [Full
text article]
Molecular Target-Guided Tumor Therapy with Natural
Products Derived from Traditional Chinese Medicine,
2007, 14, 2024-2032
Thomas Efferth, Yu-jie Fu, Yuan-gang
Zu, Günter Schwarz, Venkata Sai Badireenath Konkimalla
and Michael Wink
[Abstract] [Full
text article]
Regulation of Mast Cell Development by Inflammatory
Factors ,2007, 14, 3044-3050
Zhi-Qing Hu, Wei-Hua Zhao and Tadakatsu Shimamura
[Abstract] [Full
text article]
DNA Damage Repair and Response Proteins as Targets
for Cancer Therapy, 2008, 15, 360-367
Howard B. Lieberman
[Abstract] [Full
text article]
Granulocyte Colony-Stimulating Factor (G-CSF) in the
Mechanism of Human Ovulation and its Clinical Usefulness,
2008, 15, 604-613
S. Makinoda, N. Hirosaki, T. Waseda, H. Tomizawa and R.
Fujii
[Abstract] [Full
text article]
Of Stem Cells and Gametes: Similarities and Differences,
2008, 15, 1249-1256
Bernard A.J. Roelen and Susana M. Chuva de Sousa
Lopes
[Abstract] [Full
text article]
Epigenetic Treatment of Myelodysplastic Syndromes
and Acute Myeloid Leukemias, 2008, 15, 1274-1287
Giuseppe Leone, Francesco D’Alò,
Giuseppe Zardo, Maria Teresa Voso and Clara Nervi
[Abstract] [Full
text article]
How Insulin Receptor Substrate Proteins Regulate the
Metabolic Capacity of the Liver - Implications for Health
and Disease, 2008, 15, 1316-1329
Louise Fritsche, Cora Weigert, Hans-Ulrich Häring
and Rainer Lehmann
[Abstract] [Full
text article]
Human Endotoxemia as a Model of Systemic Inflammation,
2008, 15, 1697-1705
A.S. Andreasen, K.S. Krabbe, R. Krogh-Madsen, S. Taudorf,
B.K. Pedersen and K. Møller
[Abstract] [Full
text article]
Toward a Molecular Understanding of the Interaction
of Dual Specificity Phosphatases with Substrates: Insights
from Structure-Based Modeling and High Throughput Screening,
2008, 15, 2536-2544
Ahmet Bakan, John S. Lazo, Peter Wipf,
Kay M. Brummond and Ivet Bahar
[Abstract] [Full
text article]
Phosphoregulation of Twist1 Provides a Mechanism
of Cell Fate Control, 2008, 15, 2641-2647
Anthony B. Firulli and Simon
J. Conway
[Abstract] [Full
text article]
Abstracts
[Back to top]
Killing Time for Cancer Stem Cells (CSC): Discovery and Development
of Selective CSC Inhibitors
María Pérez-Caro and Isidro Sánchez-García
[Full text article]
Can cancer be cured or will it have to be controlled
as a chronic disease? Despite a better understanding of the
biology of tumour cells, the treatment of most cancers has
not significantly changed for the past three decades. Are
current cancer drugs targeted at the wrong kind of cells?
Accumulating evidence has implicated that cancer is a disease
of stem cells. In this context, a small fraction of cancer
cells adopt the properties of stem cells. In some cases, the
cancer stem cells (CSC) could be the close derivative of normal
tissue stem cells. In either situation, the net result will
be the same, in that CSC are the cells to be used as targets
in the development of molecular and pharmaceutical therapies
to treat and prevent human cancer. This could be a paradigm
shift in the treatment of cancer, away from targeting the
blast cells and towards the targeting of the CSC. A challenge
to this approach will be to find a way to specifically target
CSC without toxicity to normal cells. In this article, we
propose how CSC can be used in therapy programs (target identification,
drug discovery, etc.). Therefore, in the future, it might
be possible to rid a patient of all his/her cancer cells,
including the cancer stem cells.
[Back to top]
The Role of the MAGUK Protein CASK in Neural Development and
Synaptic Function
Yi-Ping Hsueh
[Full text article]
CASK, which belongs to the family of membrane-associated
guanylate kinase (MAGUK) proteins, is recognized as a multidomain
scaffolding protein highly expressed in the mammalian nervous
system. MAGUK proteins generally target to neuronal synapses
and regulate trafficking, targeting, and signaling of ion
channels. However, CASK is a unique MAGUK protein in several
respects. It not only plays a role in synaptic protein targeting
but also contributes to neural development and regulation
of gene expression. Several CASK-interacting proteins have
been identified from yeast two-hybrid screening and biochemical
isolation. These proteins, whose interactions with CASK are
reviewed here, include the Parkinson’s disease molecule
parkin, the adhesion molecule neurexin, syndecans, calcium
channel proteins, the cytoplasmic adaptor protein Mint1, Veli/mLIN-7/MALS,
SAP97, caskin and CIP98, transcription factor Tbr-1, and nucleosome
assembly protein CINAP. More important, CASK may form different
complexes with different binding partners and perform different
functions. Among these interactions, CASK, Tbr-1, and CINAP
can form a transcriptional complex regulating gene expression.
Reelin and NMDAR subunit 2b (NR2b) genes have been identified
as Tbr-1 target genes. Reelin is critical for neural development.
NR2b is an important subunit of NMDAR, which plays important
roles in neural function and neurological diseases. Regulation
of reelin and NR2b expression suggests the potential roles
of the Tbr-1-CASK-CINAP complex in neural activity, development,
and disease. The functions of these CASK protein complexes
are also discussed in detail in this review.
[Back to top]
Review Camptothecin: Current Perspectives
Qing-Yong Li, Yuan-Gang Zu, Rong-Zhen Shi and Li-Ping
Yao
[Full text article]
The review provides a detailed discussion of recent
advances in the medicinal chemistry of camptothecin, a potent
antitumor agent that targets topoisomerase I. Thousands of
CPT derivatives have been synthesized. Two of them, Topotecan
and Irinotecan, are commercially approved for use in clinic
as antitumor agents while more are still in clinic trials.
This review summarizes the current status of the modern synthetic
approaches to CPT, the mechanism of action of CPT, the structure-activity
relationship(SAR), a number of novel CPT analogs and their
biologic activity. There is a systematic evaluation of A-,
B- and E-ring- modified camptothecins reported recently.
[Back to top]
Current Progress in Non-Invasive Imaging of Beta Cell Mass
of the Endocrine Pancreas
Fabiola Souza, Matthew Freeby, Kristi Hultman, Norman Simpson,
Alan Herron,Piotr Witkowsky, Eric Liu, Antonella Maffei and
Paul E. Harris
[Full text article]
The increasing incidence of diabetes requires a
better understanding of the pathogenesis of the clinical disease.
Studies in prevention and treatment have been hampered by
the single end-point of diagnosis of diabetes and hyperglycemia.
The common pathology in both type 1 and type 2 diabetes is
insufficient beta-cell mass to meet the metabolic demand.
Unfortunately, current diagnostic methods rely on metabolic
responses that do not accurately reflect true beta-cell mass.
Recent advances in beta-cell imaging have utilized multiple
modalities in experimental and clinical settings. While no
“gold-standard” exists to measure beta-cell mass,
modalities such as single photon emission computed tomography,
optical and fluorescent imaging, magnetic resonance imaging,
and positron emission tomography have been used with mixed
success. Many of the methods are limited by the inability
to translate to the clinical setting, poor discrimination
between the exocrine and endocrine pancreas, or a poor measurement
of beta-cell mass. However, promising new “neuro-functional
imaging” approaches have emerged as improved measures
of beta-cell mass. We review the current understanding of
the pathogenesis and evaluation of diabetes, as well as experimental
approaches to assessing beta-cell mass.
[Back to top]
Anti-Galectin Compounds as Potential Anti-Cancer Drugs
Laurent Ingrassia, Isabelle Camby, Florence Lefranc, Véronique
Mathieu, Prosper Nshimyumukiza, Francis Darro and Robert Kiss
[Full text article]
Galectins form a family of carbohydrate-binding proteins
defined by their affinity for β-galactosides
containing glycoconjugates. The carbohydrate recognition domain
(CRD) is responsible for the specificity of galectins for
saccharides. This binding may result in modulated cell proliferation,
cell death and cell migration, three processes that are intimately
involved in cancer initiation and progression. Galectins can
also display protein-protein types of interactions with their
binding partners. Certain galectins directly involved in cancer
progression seem to be promising targets for the development
of novel therapeutic strategies to combat cancer. Indeed,
migrating cancer cells resistant to apoptosis still constitute
the principal target for the cytotoxic drugs used to treat
cancer patients. Reducing the levels of migration in apoptosis-resistant
cancer cells can restore certain levels of sensitivity to
apoptosis (and so to pro-apoptotic drugs) in restricted-migration
cancer cells. Anti-galectin agents can restrict the levels
of migration of several types of cancer cell and should therefore
be used in association with cytotoxic drugs to combat metastatic
cancer. We provide experimental proof in support of this concept.
While the present review focuses on various experimental strategies
to impair cancer progression by targeting certain types of
galectins, it pays particular attention to glioblastomas,
which constitute the ultimate level of malignancy in primary
brain tumors. Glioblastomas form the most common type of malignant
brain tumor in children and adults, and no glioblastoma patient
has been cured to date.
[Back to top]
Molecular Target-Guided Tumor Therapy with Natural Products
Derived from Traditional Chinese Medicine
Thomas Efferth, Yu-jie Fu, Yuan-gang Zu, Günter Schwarz,
Venkata Sai Badireenath Konkimalla and Michael Wink
[Full text article]
A tremendous interest exists in the Western world
in Traditional Chinese Medicine (TCM) with rapidly increasing
export rates of TCM products from China to Europe and USA.
This led to a national decision of the Chinese government
to implement a “Plan for the Modernization of Chinese
Medicine”. Concerning the use of Chinese medicinal herbs,
two major directions can be distinguished. One field is phytochemistry
and pharmacognosy. Secondary metabolites isolated from Chinese
plants can be easily subjected to pharmacological, molecular
biological, and pharmacogenomic analyses using methods of
modern cell and molecular biology as exemplified for camptothecin
from Camptotheca acuminata in the present review. The second
field of interest is phytomedicine. Standardized international
quality guidelines help to improve quality, safety and efficacy
of Chinese medicinal herbs. Sustainability of natural products
from TCM can be reached by breeding high-yield varieties or
by biotechnological approaches. In the long term, natural
products from TCM can contribute to the development of molecular
target-guided therapies and individualized treatment strategies.
[Back to top]
Regulation of Mast Cell Development by Inflammatory Factors
Zhi-Qing Hu, Wei-Hua Zhao and Tadakatsu Shimamura
[Full text article]
Mast cells are potent effectors playing a key role
in IgE-associated hypersensitivity reactions, allergic disorders,
inflammation and protective immune responses. Mast cell development
in vivo occurs mainly in non-hematopoietic microenvironments
and increased mast cell numbers can be seen in various inflammatory
diseases and pathologic conditions. SCF (also known as kit
ligand or KitL) and c-kit signaling are essential for both
human and murine mast cell development, while IL-3 is required
for murine mast cell hyperplasia that occurs in response to
various stimuli. Besides SCF and IL-3, the cytokines IL-4,
IL-9, IL-10 and IL-13 are also called mast cell growth factors
due to their actions synergistically promoting mast cell proliferation
and differentiation in the presence of SCF or IL-3. These
cytokines alone however are unable to support neither the
proliferation nor survival of mast cells. Most research has
focused on examining the direct effects of the above cytokines
on mast cells or their precursors. However, it is difficult
to explain the process of mast cell development only in terms
of the above mast cell growth factors. A series of experiments
in our laboratory and by others has revealed that inflammatory
mediators and cytokines, as triggers or regulators, are also
crucial for mast cell development. This review summarizes
recent progress in our understanding of how various inflammatory
factors regulate mast cell development, with particular focus
on the effects of prostaglandin E (PGE), TNF-α
, IL-6, IFN-γ
and an unknown apoptosis-inducing factor produced by IL-4-stimulated
macrophages.
[Back to top]
DNA Damage Repair and Response Proteins as Targets for Cancer
Therapy
Howard B. Lieberman
[Full text article]
The cellular response to DNA damage is critical for determining
whether carcinogenesis, cell death or other deleterious biological
effects will ensue. Numerous cellular enzymatic mechanisms
can directly repair damaged DNA, or allow tolerance of DNA
lesions, and thus reduce potential harmful effects. These
processes include base excision repair, nucleotide excision
repair, nonhomologous end joining, homologous recombinational
repair and mismatch repair, as well as translesion synthesis.
Furthermore, DNA damage-inducible cell cycle checkpoint systems
transiently delay cell cycle progression. Presumably, this
allows extra time for repair before entry of cells into critical
phases of the cell cycle, an event that could be lethal if
pursued with damaged DNA. When damage is excessive apoptotic
cellular suicide mechanisms can be induced. Many of the survival-promoting
pathways maintain genomic integrity even in the absence of
exogenous agents, thus likely processing spontaneous damage
caused by the byproducts of normal cellular metabolism. DNA
damage can initiate cancer, and radiological as well as chemical
agents used to treat cancer patients often cause DNA damage.
Many genes are involved in each of the DNA damage processing
mechanisms, and the encoded proteins could ultimately serve
as targets for therapy, with the goal of neutralizing their
ability to repair damage in cancer cells. Therefore, modulation
of DNA damage responses coupled with more conventional radiotherapy
and chemotherapy approaches could sensitize cancer cells to
treatment. Alteration of DNA damage response genes and proteins
should thus be considered an important though as of yet not
fully exploited avenue to enhance cancer therapy.
[Back to top]
Granulocyte Colony-Stimulating Factor (G-CSF) in the Mechanism
of Human Ovulation and its Clinical Usefulness
S. Makinoda, N. Hirosaki, T. Waseda, H. Tomizawa and R.
Fujii
[Full text article]
In 1980, Espey proposed a famous hypothesis that mammalian
ovulation is comparable to an inflammatory reaction and many
researches have proved the validity of his hypothesis in the
last three decades. For example, interleukin (IL)-1β,
IL-6, tumor necrosis factor (TNF)-α,
granulocyte-macrophage colony-stimulating factor (GM-CSF),
macrophage colony-stimulating factor (M-CSF) and other inflammatory
cytokines presence was proven in the preovulatory follicle.
Since granulocyte is the major leukocyte and it plays a very
important role during inflammation, the importance of granulocyte
and its related cytokine, granulocyte colony-stimulating factor
(G-CSF) in the mechanism of human ovulation is easily predictable.
G-CSF is one of the hemopoietic cytokines and it has strong
positive effects on granulocytes. G-CSF increases the number
of granulocytes and it improves the function of granulocytes.
In this review, the participation of leukocytes in the ovulation
mechanism is demonstrated first. Second, the participation
of G-CSF is shown in comparison with the above mentioned cytokines.
Finally, since G-CSF has been used for more than 20 years
as a medicine without severe side effects in the field of
oncology, the clinical application of G-CSF for the treatment
of an ovulation disorder, luteinized unruptured follicle (LUF),
will be discussed.
[Back to top]
Of Stem Cells and Gametes: Similarities and Differences
Bernard A.J. Roelen and Susana M. Chuva de Sousa
Lopes
[Full text article]
Fusion of a mammalian sperm cell with an oocyte will
lead to the formation of a new organism. As this new organism
develops, the cells that construct the organism gradually
lose developmental competence and become differentiated, a
process which is in part mediated via epigenetic modifications.
These mechanisms include DNA methylation, histone tail modifications
and association with Polycomb and Trithorax proteins. Several
cells within the organism must however maintain or regain
developmental competence while they are highly specialized.
These are the primordial germ cells that form the gametes;
the oocytes and sperm cells. In this review different epigenetic
modifying mechanisms will be discussed as they occur in developing
embryos. In addition, aspects of nuclear reprogramming that
are likely to occur via removal of epigenetic modifications
are important, and several epigenetic removal mechanisms are
indeed also active in developing germ cells.
In vivo, a pluripotent cell has the capacity to form gametes,
but in vitro terminal gametogenesis has proven to be difficult.
Although development of pluripotent cells to cells with the
characteristics of early germ cells has been unequivocally
demonstrated, creating the correct culture milieu that enables
further maturation of these cells has as yet been futile.
[Back to top]
Epigenetic Treatment of Myelodysplastic Syndromes and Acute
Myeloid Leukemias
Giuseppe Leone, Francesco D’Alò,
Giuseppe Zardo, Maria Teresa Voso and Clara Nervi
[Full text article]
Epigenetic mechanisms affecting chromatin structure contribute
to regulate gene expression and assure the inheritance of
information, which are essential for the proper expression
of key regulatory genes in healthy cells, tissues and organs.
In the medical field, an increasing body of evidence indicates
that altered gene expression or de-regulated gene function
lead to disease. Cancer cells also suffer a profound change
in the genomic methylation patterns and chromatin status.
Aberrant DNA methylation patterns, changes in chromatin structure
and in gene expression are common in all kind of tumor types.
However, studies on leukemias have provided paradigmatic examples
for the functional implications of the epigenetic alterations
in cancer development and progression as well as their relevance
for therapeutical targeting.
[Back to top]
How Insulin Receptor Substrate Proteins Regulate the Metabolic
Capacity of the Liver - Implications for Health and Disease
Louise Fritsche, Cora Weigert, Hans-Ulrich Häring and
Rainer Lehmann
[Full text article]
The liver plays a key role in glucose homeostasis, lipid
and energy metabolism. Its function is primarily controlled
by the anabolic hormone insulin and its counterparts glucagon,
catecholamines and glucocorticoids. Dysregulation of this
homeostatic system is a major cause for development of the
metabolic syndrome and type 2 diabetes mellitus. The features
of the underlying dynamic molecular network that coordinates
systemic nutrient homeostasis are less clear. But recently,
considerable progress has been made in elucidating molecular
pathways and potential factors involved in the regulation
of energy and lipid metabolism and affected in diabetic states.
In this review we will focus on important stations in the
complex network of molecules that control the balance between
glucose production, glucose utilization and regulation of
lipid metabolism. Special attention will be paid to the insulin
receptor substrate (IRS) proteins with the two major isoforms
IRS-1 and IRS-2 as a critical node in hepatic insulin signalling.
IRS proteins act as docking molecules to connect tyrosine
kinase receptor activation to essential downstream kinase
cascades, including activation of the PI-3 kinase or MAPK
cascade. IRS-1 and IRS-2 are complementary key players in
the regulation of hepatic insulin signalling and expression
of genes involved in gluconeogenesis, glycogen synthesis and
lipid metabolism. The function of IRS proteins is regulated
by their expression levels and posttranslational modifications.
This regulation within the dynamic molecular network that
coordinates systemic nutrient homeostasis will be outlined
in detail under the following conditions: after feeding, during
fasting and during exercise. Dysfunction of IRS proteins initially
leads to post-prandial hyperglycemia, increased hepatic glucose
production, and dysregulated lipid synthesis and is discussed
as major pathophysiological mechanism for the development
of insulin resistance and type 2 diabetes mellitus.
Understanding the molecular regulation and the pathophysiological
modifications of IRS proteins is crucial in order to identify
new sites for potential intervention to treat or prevent hepatic
insulin resistance and type 2 diabetes mellitus.
[Back to top]
Human Endotoxemia as a Model of Systemic Inflammation
A.S. Andreasen, K.S. Krabbe, R. Krogh-Madsen, S. Taudorf,
B.K. Pedersen and K. Møller
[Full
text article]
Systemic inflammation is a pathogenetic component in a vast
number of acute and chronic diseases such as sepsis, trauma,
type 2 diabetes, atherosclerosis, and Alzheimer’s disease,
all of which are associated with a substantial morbidity and
mortality. However, the molecular mechanisms and physiological
significance of the systemic inflammatory response are still
not fully understood. The human endotoxin model, an in
vivo model of systemic inflammation in which lipopolysaccharide
is injected or infused intravenously in healthy volunteers,
may be helpful in unravelling these issues. The present review
addresses the basic changes that occur in this model. The
activation of inflammatory cascades as well as organ-specific
haemodynamic and functional changes after lipopolysaccharide
are described, and the limitations of human-experimental models
for the study of clinical disease are discussed. Finally,
we outline the ethical considerations that apply to the use
of human endotoxin model.
[Back to top]
Toward a Molecular Understanding of the Interaction
of Dual Specificity Phosphatases with Substrates: Insights
from Structure-Based Modeling and High Throughput Screening
Ahmet Bakan, John S. Lazo, Peter Wipf,
Kay M. Brummond and Ivet Bahar
[Full
text article]
Dual-specificity phosphatases (DSPs) are important,
but poorly understood, cell signaling enzymes that remove
phosphate groups from tyrosine and serine/threonine residues
on their substrate. Deregulation of DSPs has been implicated
in cancer, obesity, diabetes, inflammation, and Alzheimer’s
disease. Due to their biological and biomedical significance,
DSPs have increasingly become the subject of drug discovery
high-throughput screening (HTS) and focused compound library
development efforts. Progress in identifying selective and
potent DSP inhibitors has, however, been restricted by the
lack of sufficient structural data on inhibitor-bound DSPs.
The shallow, almost flat, substrate binding sites in DSPs
have been a major factor in hampering the rational design
and the experimental development of active site inhibitors.
Recent experimental and virtual HTS studies, as well as advances
in molecular modeling, provide new insights into the potential
mechanisms for substrate recognition and binding by this important
class of enzymes. We present herein an overview of the progress,
along with a brief description of applications to two types
of DSPs: Cdc25 and MAP kinase phosphatase (MKP) family members.
In particular, we focus on combined computational and experimental
efforts for designing Cdc25B and MKP-1 inhibitors and understanding
their mechanisms of interactions with their target proteins.
These studies emphasize the utility of developing computational
models and methods that meet the two major challenges currently
faced in structure-based in silico design of lead
compounds: the conformational flexibility of the target protein
and the entropic contribution to the selection and stabilization
of particular bound conformers.
[Back to top]
Phosphoregulation of Twist1 Provides a Mechanism
of Cell Fate Control
Anthony B. Firulli and Simon
J. Conway
[Full
text article]
Basic Helix-loop-Helix (bHLH) factors play a significant role
in both development and disease. bHLH factors function as
protein dimers where two bHLH factors compose an active transcriptional
complex. In various species, the bHLH factor Twist has been
shown to play critical roles in diverse developmental systems
such as mesoderm formation, neurogenesis, myogenesis, and
neural crest cell migration and differentiation. Pathologically,
Twist1 is a master regulator of epithelial-to-mesenchymal
transition (EMT) and is causative of the autosomal-dominant
human disease Saethre Chotzen Syndrome (SCS). Given the wide
spectrum of Twist1 expression in the developing embryo
and the diverse roles it plays within these forming tissues,
the question of how Twist1 fills some of these specific
roles has been largely unanswered. Recent work has shown that
Twist’s biological function can be regulated by its
partner choice within a given cell. Our work has identified
a phosphoregulatory circuit where phosphorylation of key residues
within the bHLH domain alters partner affinities for Twist1;
and more recently, we show that the DNA binding affinity of
the complexes that do form is affected in a cis-element dependent
manner. Such perturbations are complex as they not only affect
direct transcriptional programs of Twist1, but they indirectly
affect the transcriptional outcomes of any bHLH factor that
can dimerize with Twist1. Thus, the resulting lineage-restricted
cell fate defects are a combination of loss-of-function and
gain-of-function events. Relating the observed phenotypes
of defective Twist function with this complex regulatory mechanism
will add insight into our understanding of the critical functions
of this complex transcription factor.
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