Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Recent studies have delineated an elaborate genetic pathway leading to CRC formation. In this pathway, a collect group of proteins called tumor suppressors manifest considerable roles. Thus, somatic or germline mutations in genes encoding adenomatous polyposis coli (APC), p53, deleted in pancreatic cancer-4 (DPC-4 or Smad4), beta-catenin, and several mismatch repair proteins, are frequently found in CRC. The exact mechanism of carcinogenesis, however, is still not entirely understood. Gut-enriched Kruppel-Like Factor (GKLF) is a newly identified zinc finger-containing transcription factor with a gut-enriched expression. Several lines of evidence suggest that GKLF is a negative regulator of cellular proliferation. First, expression of GKLF is temporally associated with conditions that promote growth arrest such as serum deprivation, contact inhibition, and DNA damage. Second, constitutive production of GKLF results in the inhibition of DNA synthesis. Third, GKLF activates the promoter of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 gene and appears to be essential in mediating the inductive effect of p52 on the p21WAF1/Cip1 promoter. Fourth, GKLF is primarily expressed in the post-mitotic epithelial cells of the intestine. Fifth, expression of GKLF is decreased in the intestine of Min mice at the stage when intestinal tumors are formed. Based on these observations, we formulated two hypotheses for the present proposal: (1) expression of GKLF is selectively decreased in intestinal tumors of humans and mice, and (2) GKLF inhibits cell growth by targeting a specific component(s) of the cell cycle. The long-term goal of this project is to understand the molecular mechanisms responsible for colorectal tumorigenesis.
Four specific aims are proposed: (1) Compare the expression of GKLF between normal and neoplastic intestinal tissues from Min mice and humans (2) Investigate the mechanisms by which GKLF negatively regulates cell growth using plasmid-mediated transfection and adenovirus-mediated gene delivery. (3) Determine the relative contribution of GKLF in mediating the transcriptional activation of the p21WAF1/Cip1 gene and cell cycle arrest caused by p53. (4) Identify additional upstream factors that regulate expression of GKLF. Successfully executed, these experiments should lead to a better insight into the molecular mechanisms of intestinal tumorigenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RAP (02))
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Mietz, Judy
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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He, Ping; Yang, Jong Won; Yang, Vincent W et al. (2018) Krüppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice. Gastroenterology 154:1494-1508.e13
Nandan, Mandayam O; Bialkowska, Agnieszka B; Yang, Vincent W (2018) KLF5 mediates the hyper-proliferative phenotype of the intestinal epithelium in mice with intestine-specific endogenous K-RasG12D expression. Am J Cancer Res 8:723-731
Kim, Chang-Kyung; He, Ping; Bialkowska, Agnieszka B et al. (2017) SP and KLF Transcription Factors in Digestive Physiology and Diseases. Gastroenterology 152:1845-1875
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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
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
Wang, K; Xu, R; Snider, A J et al. (2016) Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. Cell Death Dis 7:e2124
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 6:815-824

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