Investigation of the molecular pathways involved in intestinal epithelial differentiation

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2014
Sade Memişoğlu, Aslı
The molecular mechanisms of balanced and continuous generation of intestinal epithelial cells, is poorly understood and disruption of this balance may result in neoplastic transformation and malignant growth. Differentiation is regulated by numerous signals, which in turn regulate signaling pathways directing activation or inactivation of certain transcription factors. Perturbations like changes in Ca2+ levels, glucose or amino acid starvation result in an ER stress response, which is also implicated in the differentiation process. In addition, ER stress and autophagy pathways may function together under certain circumstances. The transcription factor C/EBPβ is of particular importance, as it is implicated in differentiation, ER stress and autophagy. In the current study, using two models of colorectal cancer cell lines, HT-29 and Caco-2 that can undergo differentiation, ER stress response was shown to be activated during the process of differentiation. Ca2+ flux into the cytoplasm was found to be the mediator of ER stress response in Caco-2 cells. Interestingly, ER stress caused induction of autophagy during differentiation in both cell lines.Moreover, C/EBPβ-3, the short isoform of C/EBPβ, was found to be one of the key players in the activation of autophagy. ER stress induced autophagy and involvement of C/EBPβ-3 in these processes was for the first time evidenced in the differentiation of Caco-2 and HT-29 cell lines. These results suggest new regulatory mechanisms that may be of significance in the process of intestinal epithelial differentiation.

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Citation Formats
A. Sade Memişoğlu, “Investigation of the molecular pathways involved in intestinal epithelial differentiation,” Ph.D. - Doctoral Program, Middle East Technical University, 2014.