The goal of this study is to define basic molecular mechanisms underlying the regulation of exocrine pancreatic cell growth by novel TIEG and BTEB Sp1-like zinc finger proteins discovered by our laboratory during the last cycle of funding. Sp1-like proteins have recently elicited significant interest because of their role in regulating gene expression, normal morphogenesis, and neoplastic transformation. Our previous observations led us to discoveries in two important areas: 1) cell growth suppression and 2) transcriptional repression. Now, our preliminary data supports a unifying theme by which these two areas may be linked, namely studies on corepressor molecules for novel Sp-like proteins. We chose this focus because of its high potential for providing novel mechanistic information that can fuel advances in our field of study. Corepressors constitute a new and exciting area of research which recently exploded after the discovery of histone-deacetylases and chromatin remodeling machines in mammalian cells. Few corepressors are known for Sp1-like proteins and nothing is known on their role in the regulation of exocrine pancreatic cell growth. Thus the central hypothesis of this proposal is that the Sp1-like zinc finger transcriptional repressors, TIEGs and BTEBs, regulate gene expression and cell growth in exocrine pancreatic cells via the interaction with distinct corepressor complexes.
Our specific aims will test the following hypothesis:
Aim 1 : Multiple corepressor interactions participate in the repression mediated by the TIEG and BTEB proteins;
Aim 2 : The transcriptional repression activity of TIEG proteins is regulated by cell signaling via the modulation of repressor corepressor interactions:
and Aim 3 : TIEG and BTEB proteins modulate pancreatic cell growth in a corepressor-dependent manner. These experiments will use state-of-the-art cellular and molecular techniques for analyzing both transcriptional repression and cell growth. We believe that focusing on corepressors makes this proposal innovative, hypothesis-driven, highly focused, and biologically- and medically-relevant, taking into consideration our expertise, previous published work, and current preliminary data. We are optimistic that the successful completion of these studies will help to build a useful theoretical framework for better understanding morphogenetic pathways that are active in exocrine pancreatic cells and that help to maintain their homeostasis regulate morphogenesis and modulate neoplastic transformation.
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