The mammalian gastrointestinal epithelium is a dynamic system in which cell proliferation is closely coupled to differentiation. Each intestinal crypt contains a single, multipotent stem cell capable of self-renewal and asymmetrical division. A majority of the descendants of the stem cell become the four cell types that constitute the gut epithelium: absorptive, goblet, enteroendocrine, and Paneth cells. Accompanying differentiation is a diminishing capacity to proliferate such that the stem cell descendants cease to divide by the time they exit the crypt. This continuum of proliferation and subsequent differentiation is subject to stringent regulation but the mechanisms are not fully understood. The grant on which this continuation application is based helped established the functions of a newly identified zinc finger-containing transcription factor called gut-enriched Kruppel-like factor (GKLF or KLF4). In the gut, expression of GKLF is found in villus cells outside the proliferating zone. A similar association with the growth-arrested state, such as that induced by serum starvation, contact inhibition, and DNA damage, is present in cultured cells. Moreover, forced expression of GKLF inhibits DNA synthesis by causing cell cycle arrest at the G1/S boundary. These findings indicate that GKLF is a potent negative regulator of cell growth. In the present grant period, we have also begun to investigate the functions of a GKLF-related protein called intestinal-enriched Kruppel-like factor (IKLF or KLF5). Expression of IKLF is acutely and transiently induced in cells treated with serum or growth factors. Forced expression of IKLF in cultured cells causes formation of foci similar to those caused by H-ras. Moreover, IKLF is found primarily in the proliferative crypt cell compartment. These results suggest that IKLF, contrary to GKLF, has a pro-proliferative effect on cells. The investigator hypothesizes that GKLF and IKLF function in a coordinated yet complementary fashion to regulate intestinal epithelial cell proliferation.
Three Specific Aims are proposed: (1) to continue to characterize the biochemical and biological functions of GKLF; (2) to determine the biological effects of IKLF on cell proliferation; and (3) to characterize the relationship between GKLF and IKLF in coordinating proliferation in the intestinal epithelium. These studies may advance the understanding of molecular mechanisms controlling proliferation of intestinal epithelial cells, and may impact on fields such as gut development and intestinal tumorigenesis.
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