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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK052230-05
Application #
6369546
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
May, Michael K
Project Start
1997-07-01
Project End
2006-06-30
Budget Start
2001-09-30
Budget End
2002-06-30
Support Year
5
Fiscal Year
2001
Total Cost
$316,024
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
He, Ping; Yang, Jong Won; Yang, Vincent W et al. (2017) Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar to Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice. Gastroenterology :
Ghaleb, Amr M; Yang, Vincent W (2017) Krüppel-like factor 4 (KLF4): What we currently know. Gene 611:27-37
Snider, Ashley J; Bialkowska, Agnieszka B; Ghaleb, Amr M et al. (2016) Murine Model for Colitis-Associated Cancer of the Colon. Methods Mol Biol 1438:245-54
Kim, Chang-Kyung; Bialkowska, Agnieszka B; Yang, Vincent W (2016) Intestinal stem cell resurgence by enterocyte precursors. Stem Cell Investig 3:49
Ruiz de Sabando, Ainara; Wang, Chao; He, Yuanjun et al. (2016) ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer. Mol Cancer Ther 15:72-83
Kuruvilla, Jes G; Kim, Chang-Kyung; Ghaleb, Amr M et al. (2016) Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following ?-Radiation-Induced Gut Injury in Mice. Stem Cell Reports 6:815-24
Ghaleb, Amr M; Elkarim, Enas A; Bialkowska, Agnieszka B et al. (2016) KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis. Mol Cancer Res 14:385-96
Nandan, Mandayam O; Ghaleb, Amr M; Bialkowska, Agnieszka B et al. (2015) Krüppel-like factor 5 is essential for proliferation and survival of mouse intestinal epithelial stem cells. Stem Cell Res 14:10-9
Kuruvilla, Jes G; Ghaleb, Amr M; Bialkowska, Agnieszka B et al. (2015) Role of Krüppel-like factor 5 in the maintenance of the stem cell niche in the intestinal crypt. Stem Cell Transl Investig 2:
Jiang, Wei-Cheng; Cheng, Yu-Hao; Yen, Meng-Hua et al. (2014) Cryo-chemical decellularization of the whole liver for mesenchymal stem cells-based functional hepatic tissue engineering. Biomaterials 35:3607-17

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