The myc proto-oncogene functions normally in control of cell proliferation and, when deregulated, is profoundly involved in the genesis of a wide spectrum of tumors. The Myc protein is a bHLHZ class transcription factor which binds DNA through dimerization with the small bHLHZ protein, Max. Myc is but one of several bHLHZ proteins (including the Mad family) which interact with Max and together comprise the Max transcription factor network. Interestingly the members of this regulatory network function as transcriptional activators or repressors and act to buffer or antagonize each others functions. The transcriptional activities of these proteins are mediated by direct recruitment of corepressors (Mad-Max recruits the mSin3-HDAC co- repressor complex to DNA) or co-activators. This application is directed towards understanding the molecular mechanisms through which specific components of the network function and their biological roles in cell proliferation, growth, differentiation, development, and oncogenesis.
The first Aim i s focused on the role of the mSin3-HDAC repression complex which is involved in gene repression related to differentiation and signal transduction. The basis for the specific interaction between defined regions of mSin3 with specific transcription factors (such as Mad) will be elucidated and used to define altered specificity mutants. The broad developmental role of mSin3A will be assessed through targeted gene deletion in mice.
Aim 2 employs the power of Drosophila to understand more deeply the functions of the network as a whole. Our earlier work demonstrated that Drosophila and vertebrate Myc play direct roles in regulating cell growth (size). We propose to employ endoreplicating larval cells to delineate the key components in the dMyc and dMad growth regulation pathways. This will be done in part by characterizing null mutations in dmyc and dmad. We will analyze direct chromatin binding of Max network proteins.
In Aim 3 we will use retroviral "gene tagging" in myc transgenic mice with defined genetic backgrounds in order to identify and characterize genes that cooperate with myc during lymphomagenesis. We will identify myc-cooperating genes under conditions of increased sensitivity to apoptosis (i.e. mdm2 hypomorphic mutant mice) or under conditions where myc function is no longer antagonized by Mad proteins (i.e. mad knockout mice). Such genes are expected to define new functional pathways for myc in tumors. PERFORMANCE StTE(S) (organization, city, state) Fred Hutchinson Cancer Research Center Covance Research Products 1100 Fairview Ave North 465 Swampbridge Road P.O. Box 19024 Denver, PA 17517 Seattle, WA 98109-1024 KEY PERSONNEL. See instructions, Use continuation pages as neededto provide the required information in Start with Principal Investigator, List all other key personnel in alphabetical order, last name first. Name Organization Eisenman, Robert N., Ph.D. Fred Hutchinson Cancer Research Center Bussemaker, Harmen Jan Columbia University Cowley, Shaun, Ph.D. Fred Hutchinson Cancer Research Center Edgar, Bruce, Ph.D. Fred Hutchinson Cancer Research Center Mendrysa, Susan, Ph.D. Fred Hutchinson Cancer Research Center Oryan, Amir, M.D., Ph.D. Fred Hutchinson Cancer Research Center Parkhurst, Susan, Ph.D. Fred Hutchinson Cancer Research Center Pierce, Sarah, Ph.D. Fred Hutchinson Cancer Research Center Radhakrishnan, Ishwar, Ph.D. Northwestern University Secombe, Jutie, Ph.D. Fred Hutchinson Cancer Research Center Shiio, Yuzuru, M.D., Ph.D. Fred Hutchinson Cancer Research Center Disclosure Permission Statement. Applicable to SBIPJSTTR Only. See instructions. [] Yes [] the format shown below. Role on Project Principal Investigator Co-Investigator Research Associate Co-Investigator Research Associate Research Associate Co-Investigator Research Associate Co-Investigator Research Associate Research Associate No PHS 398 (Rev. 05/01) Page _2 Form Page 2 a Principal Investigator/Program Director (Last, first, middle): Eisenman, Robert N. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page, RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37CA057138-22S1
Application #
8724703
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mietz, Judy
Project Start
1991-09-30
Project End
2013-12-31
Budget Start
2012-07-01
Budget End
2013-12-31
Support Year
22
Fiscal Year
2013
Total Cost
$35,000
Indirect Cost
$15,134
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Conacci-Sorrell, Maralice; McFerrin, Lisa; Eisenman, Robert N (2014) An overview of MYC and its interactome. Cold Spring Harb Perspect Med 4:a014357
Young, Susan L; Diolaiti, Daniel; Conacci-Sorrell, Maralice et al. (2011) Premetazoan ancestry of the Myc-Max network. Mol Biol Evol 28:2961-71
Li, Ling; Greer, Christina; Eisenman, Robert N et al. (2010) Essential functions of the histone demethylase lid. PLoS Genet 6:e1001221
Pierce, Sarah B; Yost, Cynthia; Anderson, Sarah A R et al. (2008) Drosophila growth and development in the absence of dMyc and dMnt. Dev Biol 315:303-16
Weber, Axel; Marquardt, Judith; Elzi, David et al. (2008) Zbtb4 represses transcription of P21CIP1 and controls the cellular response to p53 activation. EMBO J 27:1563-74
Secombe, Julie; Eisenman, Robert N (2007) The function and regulation of the JARID1 family of histone H3 lysine 4 demethylases: the Myc connection. Cell Cycle 6:1324-8
Orian, Amir; Delrow, Jeffrey J; Rosales Nieves, Alicia E et al. (2007) A Myc-Groucho complex integrates EGF and Notch signaling to regulate neural development. Proc Natl Acad Sci U S A 104:15771-6
Secombe, Julie; Li, Ling; Carlos, Leni et al. (2007) The Trithorax group protein Lid is a trimethyl histone H3K4 demethylase required for dMyc-induced cell growth. Genes Dev 21:537-51
Shiio, Yuzuru; Rose, David W; Aur, Radin et al. (2006) Identification and characterization of SAP25, a novel component of the mSin3 corepressor complex. Mol Cell Biol 26:1386-97
Pierce, Sarah B; Yost, Cynthia; Britton, Jessica S et al. (2004) dMyc is required for larval growth and endoreplication in Drosophila. Development 131:2317-27

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