Our long term goal is to discover mechanisms that mediate silencing of tumor suppressor pathways during the development of pancreatic cancer, the 4th leading cause of death by cancer in USA and an extremely painful disease. Congruent with this goal, this proposal seeks to define basic mechanisms underlying the regulation of exocrine pancreatic cell growth by novel TGF?-inducible KLF zinc finger repressor proteins discovered by our laboratory. KLF 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 three important areas: 1) cell growth suppression, 2) transcriptional repression, and 3) TGF? ?signaling. Now, our preliminary data supports a unifying theme by which these three areas may be linked, namely studies on novel coregulator molecules for KLF11 (the structural and functional paradigm of this subfamily of TGF?-inducible KLF repressors) and their role in modulating the expression of members of the TGF? superfamily of signaling molecules. 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, methylases, and chromatin remodeling machines in mammalian cells. Few corepressors are known for KLF proteins, and rudimentary knowledge is available on their role in the regulation of exocrine pancreatic cell growth and diseases. Thus our central hypothesis is that novel protein interactions modulate the function of KLF11 in gene expression and/or cell growth regulation, as well as neoplastic transformation via the regulation of members from the TGF? ?superfamily of signaling molecules.
Our aims will test the following hypothesis:
Aim 1 : Interaction with HP1 modulates the ability of KLF11 to regulate gene expression, cell growth, and neoplastic transformation;
Aim 2 : Interaction with the G protein ? subunit modulates the ability of KLF11 to regulate gene expression, cell growth, and neoplastic transformation, and;
Aim 3 : KLF11 regulates the expression of targets from the TGF? family of signaling proteins known to be involved in the regulation of normal cell growth and/or neoplastic transformation. These experiments will use state-of-the-art cellular and molecular techniques for analyzing both transcriptional repression and cell growth. We believe that linking corepressors with cell growth regulation and TGF? signaling makes this proposal innovative, hypothesis driven, highly focused, biologically and medically relevant, and feasible taking into consideration our expertise, previous published work, and current preliminary data. We are optimistic 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 help to maintain their homeostasis, regulate morphogenesis, and modulate neoplastic transformation.
These investigations represent a defined strategy to discover how pancreatic cancer, a painful and deadly disease that ranks 4th as the cause of death by cancer in USA, arises. Patients affected by this cancer die within 3 to 6 months after the diagnosis, and currently, no effective treatment exists for this disease. However, we are optimistic that our studies will build the foundation for future treatment and perhaps even the prevention of this disease.
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