A common cause of neoplastic transformation and subsequent tumor formation/progression involves deregulation of gene expression via alteration of transcription factor function. The SNAG repression domain, named for its presence in the snail/GFI-1 class of zinc finger transcription factors, is present in a variety of proto-oncogenic transcription factors and developmental regulators. T h e p rototype SNAG domain-containing oncogene, GFI-1 (growth-factor i ndependence-1) is responsible for development of T-cell thymomas. Significantly, these oncogenic functions require a functional SNAG repression domain. However, the molecular mechanisms of SNAG-mediated transcriptional repression, which is responsible for these biological functions are completely unknown. The major goal of this proposal is to completely characterize and define the mechanism of the novel SNAG domain in transcriptional regulation, cell growth and tumorigenesis. In the preliminary data to support this proposal, we have presented evidence for a specific interaction between SNAG repression domain and the LIM domains of Ajuba, which can function as a novel SNAG corepressor. Ajuba shuttles between the cytoplasm and nucleus and may form a novel intracellular signaling system. Ajuba interacts with SNAG in v i vo, co-localizes with it and enhances SNAG-mediated transcriptional repression. We postulate that, in this molecular interaction, Ajuba may function as a scaffold for the assembly of a macromolecular repression complex at the target promoters while the SNAG domain may serve as a nuclear targeting motif in the transport of Ajuba into the nucleus.
The specific aims of this proposal will: 1) provide a high resolution definition of the SNAG-Ajuba molecular interaction; 2) biochemically identify the endogenous SNAG-Ajuba complexes; and 3) define the biological significance of SNAG-Ajuba mediated repression. The information derived from the proposed research will significantly advance our understanding of the role of SNAG zinc-finger transcription factors in transcriptional control of cell growth, and the role of these processes in neoplastic transformations as well as a knowledge about possible therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01CA095620-03
Application #
6801961
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2002-09-27
Project End
2007-08-31
Budget Start
2004-09-29
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$155,979
Indirect Cost
Name
Florida Atlantic University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
004147534
City
Boca Raton
State
FL
Country
United States
Zip Code
33431
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Chiang, Cindy; Ayyanathan, Kasirajan (2013) Snail/Gfi-1 (SNAG) family zinc finger proteins in transcription regulation, chromatin dynamics, cell signaling, development, and disease. Cytokine Growth Factor Rev 24:123-31
Chiang, C; Ayyanathan, K (2012) Characterization of the E-box binding affinity to snag-zinc finger proteins. Mol Biol (Mosk) 46:907-14
Ayyanathan, Kasirajan; Kesaraju, Shailaja; Dawson-Scully, Ken et al. (2012) Combination of sulindac and dichloroacetate kills cancer cells via oxidative damage. PLoS One 7:e39949
Krystel, Joseph; Ayyanathan, Kasirajan (2012) An efficient and cost-effective protocol for selecting transcription factor binding sites that reduces isotope usage. J Biomol Tech 23:40-6
Hou, Zhaoyuan; Peng, Hongzhuang; Ayyanathan, Kasirajan et al. (2008) The LIM protein AJUBA recruits protein arginine methyltransferase 5 to mediate SNAIL-dependent transcriptional repression. Mol Cell Biol 28:3198-207
Ayyanathan, Kasirajan; Peng, Hongzhuang; Hou, Zhaoyuan et al. (2007) The Ajuba LIM domain protein is a corepressor for SNAG domain mediated repression and participates in nucleocytoplasmic Shuttling. Cancer Res 67:9097-106
Ayyanathan, Kasirajan; Lechner, Mark S; Bell, Peter et al. (2003) Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev 17:1855-69