Mechanism of beta-Catenin-mediated Transcriptional Regulation of Epidermal Growth Factor Receptor Expression in Glycogen Synthase Kinase 3 beta-inactivated Prostate Cancer Cells

作者：Guturi Kiran Kumar Naidu; Mandal Tapashi; Chatterjee Anirban; Sarkar Moumita; Bhattacharya Seemana; Chatterjee Uttara; Ghosh Mrinal K^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287(22): 18287-18296.

DOI：10.1074/jbc.M111.324798

Wnt/beta-catenin and EGFR pathways are important in cancer development and often aberrantly activated in human cancer. However, it is very important to understand the mechanism responsible for this activation and the relation between them. Here, we report the mechanism of EGFR expression by transcriptionally active beta-catenin in GSK3 beta-inactivated prostate cancer cells that eventually leads to its enhanced proliferation and survival. Expressions of beta-catenin and EGFR are elevated in various cancers specifically in prostate cancer cells, DU145. When GSK3 beta is inactivated in these cells, beta-catenin gets stabilized, phosphorylated at Ser-552 by protein kinase A, accumulates in the nucleus, and regulates the expression of its target genes that include EGFR. Chromatin immunoprecipitation (ChIP) and promoter analysis revealed that the EGFR promoter gets occupied by transcriptionally active beta-catenin when elevated in GSK3 beta-inactivated cells. This phenomenon not only leads to increased expression of EGFR but also initiates the activation of its downstream molecules such as ERK1/2 and Stat3, ultimately resulting in up-regulation of multiple genes involved in cell proliferation and survival.

• 出版日期2012-5-25