Colorectal carcinogenesis is a multi-step processes including the activation of oncogenes and the loss of tumor suppressor genes. Although a serial of gene mutations were identified during colorectal carcinogenesis, the cellular and molecular events governing cell growth in the colon remained poorly understood. Gut-enriched krupple-like factor (GKLF/KLF4) is a newly identified zinc-finger transcription factor, and is expressed extensively in the gastrointestinal tract. Several studies have shown that GKLF is potentially a negative regulator of cell proliferation, however, the signaling pathways of its action are still unclear. Studies from our laboratory have recently demonstrated that interferon-gamma (IFN-gamma) stimulated GKLF mRNA and protein levels in a dose-and time-dependent manner and that enhanced GKLF expression was associated with IFN-gamma -promoted growth inhibition and apoptosis. These findings will allow us to use this model to examine the signaling pathways regulating GKLF expression. Moreover, GKLF inhibited ornithine decarboxylase (ODC) promoter activity, and this effect was attenuated by a histone deacetylase inhibitor. These data suggested that the growth-arrest property of GKLF might be mediated through the interaction with ODC promoter via the recruitment of histone deacetylase and the modification of the chromatin structure. We therefore propose that binding of IFN-gamma to its receptor induces dimerization of the receptors, resulting in activation of the receptor-associated Janus tyrosine kinases JAK1 and JAK2. The JAK1 and JAK2 activate a latent cytoplasmic protein, STAT1, and allow the STAT1 protein to translocate to the nucleus and interact with IFN-gamma -responsive genes, including GKLF. The induction of GKLF expression will then inhibit the transactivation of ODC gene through the recruitment of histone deacetylase (HDAC) and result in cell cycle arrest at the G1/S phase and growth inhibition. To examine these hypotheses, we propose the following studies:
Aim 1. To investigate the involvement of STAT1 signaling in IFN-gamma -mediated GKLF expression.
Aim 2. To identify ODC as a potential downstream target of GKLF signaling.
Aim 3. To explore the contribution of histone deacetylase on GKLF-regulated ODC gene expression. Collectively, the information gained from this proposal will add an important new information regarding the signaling pathways of GKLF-mediated growth arrest. Ultimately, if the GKLF down-regulation process can be manipulated, it may be possible to use inhibitors of this process for chemoprevention of cancer formation in the gastrointestinal tract.
| Chen, Zhi Yi; Wang, Xuesheng; Zhou, Yunhong et al. (2005) Destabilization of Kruppel-like factor 4 protein in response to serum stimulation involves the ubiquitin-proteasome pathway. Cancer Res 65:10394-400 |
| Chen, Zhi Yi; Rex, Sybille; Tseng, Chi-Chuan (2004) Kruppel-like factor 4 is transactivated by butyrate in colon cancer cells. J Nutr 134:792-8 |
