Mechanism of β-Catenin-mediated Transcriptional Regulation of Epidermal Growth Factor Receptor Expression in Glycogen Synthase Kinase 3 β-inactivated Prostate Cancer Cells
Mechanism of β-Catenin-mediated Transcriptional Regulation of Epidermal Growth Factor Receptor Expression in Glycogen Synthase Kinase 3 β-inactivated Prostate Cancer Cells
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DOI：
10.1074/jbc.m111.324798
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发表时间：
2012-05-25
影响因子：
4.8
通讯作者：
Ghosh, Mrinal K.
中科院分区：
文献类型：
--
作者：
Guturi, Kiran Kumar Naidu;Mandal, Tapashi;Ghosh, Mrinal K.
Wnt/ β -连环蛋白和EGFR通路在癌症发展中很重要，并且在人类癌症中经常异常激活。然而，了解这种激活的机制以及它们之间的关系是非常重要的。在这里，我们报道了EGFR在GSK3 β失活的前列腺癌细胞中通过转录活性β -连环蛋白表达的机制，最终导致其增殖和存活增强。β -连环蛋白和EGFR的表达在多种癌症中升高，特别是在前列腺癌细胞中。当GSK3 β在这些细胞中失活时，β -连环蛋白得到稳定，在Ser-552位点被蛋白激酶A磷酸化，在细胞核中积累，并调节包括EGFR在内的靶基因的表达。染色质免疫沉淀（ChIP）和启动子分析显示，EGFR启动子在GSK3 β失活细胞中升高时被转录活性β -连环蛋白占据。这种现象不仅导致EGFR的表达增加，还会激活其下游分子ERK1/2、Stat3等，最终导致多个参与细胞增殖和存活的基因上调。
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.