Our understanding of cancer initiation far exceeds our knowledge of tumor progression. The cell adhesion molecule E-cadherin contributes to aspects of tumor formation and invasion. The DNA-binding proteins Snail and Slug mediate E-cadherin transcriptional repression, and regulate aspects of carcinogenesis and cell survivability. While much has been learned regarding Snail and Slug biological function, the molecular mechanisms of Snail and Slug mediated transcriptional repression are not well understood. The studies in this proposal aim to determine the molecular mechanisms of Snail and Slug repression in the context of the E-cadherin promoter. First, specific activation of the E-cadherin promoter will be reconstituted in vitro, followed by biochemical studies to elucidate the mechanisms of Snail and Slug repression of E-cadherin. Finally, studies in vivo will be performed to complement the biochemical approaches, and examine E-cadherin transcriptional regulation in living cells. These studies will provide insight into the basis of Snail and Slug repression and E-cadherin silencing, and may potentially identify key components of tumor establishment and invasion.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32GM071166-04
Application #
7281138
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Haynes, Susan R
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2006-09-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$30,947
Indirect Cost
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Sims 3rd, Robert J; Rojas, Luis Alejandro; Beck, David B et al. (2011) The C-terminal domain of RNA polymerase II is modified by site-specific methylation. Science 332:99-103
Sims 3rd, Robert J; Millhouse, Scott; Chen, Chi-Fu et al. (2007) Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. Mol Cell 28:665-76
Trojer, Patrick; Li, Guohong; Sims 3rd, Robert J et al. (2007) L3MBTL1, a histone-methylation-dependent chromatin lock. Cell 129:915-28
Reinberg, Danny; Sims 3rd, Robert J (2006) de FACTo nucleosome dynamics. J Biol Chem 281:23297-301
Sims 3rd, Robert J; Trojer, Patrick; Li, Guohong et al. (2006) Methods to identify and functionally analyze factors that specifically recognize histone lysine methylation. Methods 40:331-8
Lewis, Brian A; Sims 3rd, Robert J; Lane, William S et al. (2005) Functional characterization of core promoter elements: DPE-specific transcription requires the protein kinase CK2 and the PC4 coactivator. Mol Cell 18:471-81
Sims 3rd, Robert J; Chen, Chi-Fu; Santos-Rosa, Helena et al. (2005) Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains. J Biol Chem 280:41789-92
Sims 3rd, Robert J; Belotserkovskaya, Rimma; Reinberg, Danny (2004) Elongation by RNA polymerase II: the short and long of it. Genes Dev 18:2437-68