Next week's Transcription Conference will be virtually run by Ligand:
September 23-24, 1997 ú San Diego Hilton Beach and Tennis Resort ú San Diego, CA
Faculty | Agenda
Chairpersons:
Richard A. Heyman, Ph.D., Senior Director, Department of Retinoid Research, Ligand
Pharmaceuticals, Inc.
Jonathan Rosen, Ph.D., Senior Director, Transcription Research Department, Ligand
Pharmaceuticals, Inc.
James M. Trzaskos, Ph.D., Director, Inflammatory Diseases Research, The DuPont Merck
Pharmaceutical Company
Speakers:
Melanie H. Cobb, Ph.D.,
Professor,
Department of Pharmacology,
UT Southwestern Medical
Center-Dallas
Gerald R. Crabtree, M.D.,
Professor,
Pathology and Developmental
Biology,
Howard Hughes Medical Institute,
Stanford University School of
Medicine
Brian D. Dynlacht, Ph.D.,
Assistant Professor,
Molecular and Cellular Biology
Department,
Harvard University
Ronald M. Evans, Ph.D.,
Professor, The Salk Institute,
Investigator, Howard Hughes
Medical Institute
Timothy Hoey, Ph.D.,
Scientist, Biology Department,
Tularik, Inc.
James T. Kadonaga, Ph.D.,
Professor,
Department of Biology,
University of California, San
Diego
Michael Karin, Ph.D.,
Professor,
Department of Pharmacology,
University of California, San
Diego
Lynn J. Ransone, Ph.D.,
Group Leader,
Experimental Therapeutics,
Signal Pharmaceuticals, Inc.
Charles T. Roberts, Jr., Ph.D.,
Professor and Associate Chairman
for Research,
Department of Pediatrics,
Oregon Health Sciences University
School of Medicine,
Doernbecher Children's Hospital
Craig M. Thompson, Ph.D.,
Senior Scientist,
SCRIPTGEN Pharmaceuticals, Inc.
Richard Ulevitch, Ph.D.,
Professor and Chairman,
Department of Immunology,
The Scripps Research Institute
Tuesday, September 23, 1997
2:15
Registration and Poster/Exhibit Set-Up/Viewing
3:15
Chairperson's Opening Remarks
Jonathan Rosen, Ph.D., Senior Director, Transcription Research Department,
Ligand Pharmaceuticals, Inc.
3:25
Drug Discovery Based on JAK/STAT Signaling Pathways
Jonathan Rosen, Ph.D.
Cytokines appear to play a key role in the pathophysiology of various disease states. In
addition to cytokines such as the interferons and hematopoietic growth factors, which
have proven to be very successful in the clinic, several additional cytokines are thought
to have clinical potential as anti-inflammatory agents. Recent breakthroughs in the
understanding of cytokine signal transduction mediated by JAK/STAT pathways has
led to the identification of new targets and approaches to discovering orally
bioavailable, small molecule drugs that modulate the action of cytokines, including many
that are thought to mediate or ameliorate inflammatory disease.
3:55
Mechanisms of Transcriptional Regulation During the Immune Response
Timothy Hoey, Ph.D., Scientist, Biology Department, Tularik, Inc.
IL-12 functions a key regulator of T-cell differentiation during the immune response.
Genetic and biochemical experiments have shown that STAT4 is required for IL-12
induced gene regulation. We are studying mechanisms of transcriptional activation of
the IFN-[gamma] gene, which is regulated by IL-12 in combination with other signals,
such as the TCR, IL-2 and TNF. Currently, we are investigating interactions between
STAT4 and other transcription factors that mediate these signals, including NFAT,
AP-1, ATF and NF-[kappa]B family members.
4:25
Functional Characterization of a Novel T-Cell Specific Transcription Factor
Inhibitor
Lynn J. Ransone, Ph.D., Group Leader, Experimental Therapeutics, Signal
Pharmaceuticals, Inc.
The transcription factor AP-1 plays an integral role in the regulation of IL-2
production, while NF-[kappa]B is essential for the transcriptional regulation of the
pro-inflammatory cytokines. Using high-throughput screening assays and combinatorial
chemistry, a novel small molecule (SP100030) was discovered that inhibits both AP-1
and NF-[kappa]B mediated gene expression. SP100030 selectively inhibits the
production of IL-2, IL-8, TNF-[alpha], and GM-CSF mRNA and protein in T-cells in
an inducer independent manner. Compound treated T-cells express diminished
amounts of AP-1 and NF-[kappa]B. These results demonstrate the potential for
transcription factors as drug discovery targets with therapeutic applications.
4:55
Close of Day Two
Wednesday, September 24, 1997
8:00
Poster/Exhibit Viewing, Coffee and Breakfast Bakeries
8:30
Chairperson's Remarks
James M. Trzaskos, Ph.D., Director, Inflammatory Diseases Research, The
DuPont Merck Pharmaceutical Company
8:40
Identification of a Novel Inhibitor of AP-1 Mediated Gene Activation
James M. Trzaskos, Ph.D.
We have identified U0126 as an inhibitor of AP-1 transactivation by screening
compounds in a cell-based reporter assay system. In vitro, U0126 directly inhibits the
MAP kinase family members, MEK1 and MEK2, and reduces ERK activity in
stimulated cells. The implications of MEK as a therapeutic target will be discussed.
9:10
Regulation and Structure of MAP Kinases
Melanie H. Cobb, Ph.D., Professor, Department of Pharmacology, UT
Southwestern Medical Center-Dallas
We have solved the crystal structure of the doubly phosphorylated form of the MAP
kinase ERK2 to understand the basis of the activation of this protein kinase family.
Regulation of this and other related signaling pathways will be discussed.
9:40
The Calcium/Calcineurin Signaling Pathway in Development and Cell
Proliferation: From Membrane to Membrane to Nucleus
Gerald R. Crabtree, M.D., Professor, Pathology and Developmental Biology,
Howard Hughes Medical Institute, Stanford University School of Medicine
10:10
Poster/Exhibit Viewing and Refreshment Break
Work will be described that traces the signal from receptors on the cell surface
through the Vav protooncogene to actin polymerization and the activation of the
transcriptional potential of the NF-AT family of transcriptional factors.
10:40
Interplay Between the E2F Transcription Factor and Kinases that Regulate
the Cell Cycle
Brian D. Dynlacht, Ph.D., Assistant Professor, Molecular and Cellular Biology
Department, Harvard University
The E2F transcription factor plays a critical role in cell cycle progression. The activity
of this protein is modulated by the retinoblastoma (pRB) tumor suppressor family of
proteins and cyclin-dependent kinases that associate with E2F. How these growth
suppressors and kinases specifically regulate E2F will be discussed.
11:10
Chromatin Structure and Transcriptional Regulation
James T. Kadonaga, Ph.D., Professor, Department of Biology, University of
California, San Diego
The regulation of transcription by RNA polymerase II is determined not only by the
action of transcription factors, but also by the structure of the chromatin template. The
packaging of DNA into chromatin restricts the accessibility of the template to the
basal transcriptional machinery, and promoter- and enhancer-binding factors function,
at least in part, to counteract the chromatin-mediated repression, (a process that is
sometimes referred to as `antirepression'). I will describe recent studies of the role of
chromatin structure and assembly in the mechanism of transcriptional regulation by
sequence-specific transcription factors.
11:40
Sensitization of Type II Diabetic Mice to Insulin by Rexinoids; Retinoid X
Receptor Selective Agonists
Richard A. Heyman, Ph.D., Senior Director, Department of Retinoid Research,
Ligand Pharmaceuticals, Inc.
Retinoic acid receptors, (RAR), thyroid hormone receptors, (TR), and peroxisome
proliferator activated receptors, (PPARs) bind to DNA to regulate transcription as
heterodimers with the retinoid X receptor (RXR). These observations lead to the
prediction that rexinoids (e.g. RXR selective agoinsts) may replicate the activity of
ligands for several of these receptors. Since PPAR[gamma] is a target for antidiabetic
agents, we investigated whether RXR ligands would alter insulin and glucose signaling.
RXR selective ligands activate RXR:PPAR[gamma] dimers. In mouse models of
non-insulin dependent diabetes mellitus (NIDDM) and obesity, RXT agonists function
as insulin sensitizers decreasing hyperglycemia, hypertriglyceridemia and
hyperinsulinemia. These data suggest that rexinoids may be effective in the treatment
of NIDDM by functioning as insulin sensitizers.
12:10
Luncheon
2:00
Chairperson's Remarks
Richard A. Heyman, Ph.D., Senior Director, Department of Retinoid Research,
Ligand Pharmaceuticals, Inc.
2:10
Positive and Negative Regulation by Nuclear Hormone Receptors
Ronald M. Evans, Ph.D., Professor, The Salk Institute, Investigator, Howard
Hughes Medical Institute
This discussion will be focused on how intracellular receptors can be used in
automated screening assays to discover new hormones controlling metabolism.
2:40
Signal Transduction From Cell Surface to the Nucleus: MAP Kinases and
AP-1
Michael Karin, Ph.D., Professor, Department of Pharmacology, University of
California, San Diego
AP-1 is a sequence specific transcriptional activator composed of Jun and Fos
subunits. AP-1 activity is present in most cell types prior to their stimulation, but it is
further induced in response to external stimuli, resulting in induction of AP-1 target
genes. Both physiological and pathological stimuli induce AP-1 activity, which is
involved in mitogenesis, differentiation, transformation and inflammation. Both
transcriptional and post-transcriptional mechanisms contribute to induction of AP-1
activity. Many of the genes encoding AP-1 components are immediate early genes.
The activity of both newly synthesized and pre-existing AP-1 components is
modulated through their post-translational modification. A key role in stimulation of
AP-1 activity is played by various mitogen activated protein kinases (MAPKs). The
activities of these enzymes are rapidly stimulated in response to various extracellular
signals through activation of MAPK modules consisting of a MAPK, a MAPK kinase
and a MAPK kinase kinase. Other MAPKs, the JNKs, are activated by growth
factors, cytokines and stressors. So far the JNKs have two known nuclear targets,
c-Jun and ATF2.
3:10
Biological Consequences of Activation of the MAP Kinase Pathways
Richard Ulevitch, Ph.D., Professor and Chairman, Department of Immunology,
The Scripps Research Institute
This talk will describe studies which investigate how signals generated at the cell
surface by recognition of phlogistic stimuli are integrated at the level of the MAP
kinase pathways. The specific emphasis will be on information derived from studies of
the effects of bacterial endotoxin (lipopolysaccharide, LPS) on cells of the innate
immune system.
3:40
Poster/Exhibit Viewing and Refreshment Break
4:10
Microbial Gene Transcription as a Therapeutic Target
Craig M. Thompson, Ph.D., Senior Scientist, SCRIPTGEN Pharmaceuticals,
Inc.
Despite intensive research spanning the past century, infectious disease remains the
third leading cause of death worldwide and the evolution of drug resistant strains adds
to this unmet medical need. Although elements of the transcriptional apparatus that are
conserved among bacterial or fungal etiologic agents differ markedly from the human
transcription machinery in ways that could be exploited by small molecules, relatively
few antibiotics work by this mechanism. SCRIPTGEN's genetic and biochemical
research has identified and validated novel targets for antibacterial and antifungal
therapeutics within the transcription apparatus. Mechanism based high-throughput
screens for small molecules that selectively inhibit these targets have identified agents
that potently and specifically inhibit microbial transcription in vitro, have antimicrobial
activity against a broad spectrum of organisms in culture, including strains resistant to
current therapeutics, and are efficacious and well-tolerated in animal models of
infectious disease.
4:40
Regulation of IGF Signal Transduction by Tumor Suppressors
Charles T. Roberts, Jr., Ph.D., Professor and Associate Chairman for Research,
Department of Pediatrics, Oregon Health Sciences University School of
Medicine, Doernbecher Children's Hospital
The IGF-I receptor that mediates the growth-promoting effects of the insulin-like
growth factors is required for transformation by EGF, src, and SV40 T antigen, and is
over-expressed in many cancers. We have previously demonstrated that the WT1
Wilms' tumor suppressor negatively regulates IGF-I receptor gene expression and
thus controls cell-surface IGF-I receptor number and the cellular response to IGFs.
Loss of WT1 function and the resultant up-regulation of IGF-I receptor levels
appears to contribute to the development of Wilms' tumor, breast carcinoma and
benign prostatic hyperplasia.
5:10
Close of Transcriptional Regulation Conference
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