Gastrointestinal Cell Proliferation and Cell Cycle

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DESCRIPTION (provided by applicant): TGF-beta is an important regulator of G1/S cell cycle progression of mammalian cells in culture. Signaling and modulation of TGF-beta dependent inhibition of cyclin-dependent kinases (cdks) and c-myc with G1 arrest, occurs through Smads. Smad2, SmadS and Smad4 are key proteins involved in gastrointestinal cell proliferation. Germline mutations in Smad2 and Smad4 result in a predisposition of the individuals to the development of gastrointestinal carcinoma. We have shown that disruption of elf, a beta-Spectrin disrupts TGF-beta signaling through SmadS and Smad4. Moreover, double heterozygotes of elf and Smad4 (elf+/-/Smad4+/-) develop earlier gastric hyperplasia and tumors. To gain further insight into the role of elf/Smad4 in cell cycle regulation and neoplasia, we propose: (1) to carry out a detailed characterization of gastric cells and mouse embryonic fibroblasts (MEFs) derived from elf/~/Smad4+/- mice to determine the effect of loss of ELF on cell cycle kinetics, ability of these cells to undergo senescence, susceptibility of gastric cells and fibroblasts to apoptotic stimuli; and susceptibility of gastric cells and MEFs to neoplastic transformation by oncogenes. (2) To determine the molecular basis for the enhanced susceptibility of the elf/Smad4+/- mice to the development of tumors and determine the nature of secondary events that lead to tumor formation. (3) To investigate the collaboration between the elf/Smad4 and p53 pathways, using elf+/-/Smad4+/- and Smad4+/- mice and mice deficient in p53. (4) To extend experiments described in Aim 1 to whole animal model systems by determining enhanced susceptibility of the elf/~/Smad4+/- and Smad4+/- mice to the development of carcinomas following treatment with chemical carcinogens such as MNU and/or DMBA, and H. pylori VacA toxin, and carrying out experiments aimed at determining the molecular basis for enhanced susceptibility to neoplasia in the elf/'/Smad4+/- and Smad4+/- mice.