CDK8 is a colorectal cancer oncogene that regulates b-catenin activity (Nature, 2008, 455:547-551)

報告日期: 2009/03/27
報告時間: 16:00/16:50
報告學生: 李育誠
講評老師: 呂增宏

CDK8 is a colorectal cancer oncogene that regulates b-catenin activity


Nature 2008, 455, 547 - 543


Speaker: 李育誠

Commentator: 呂增宏老師

Time: 2009/3/27 16:00-16:50

Room: 602



    The WNT-β-catenin signaling pathway is aberrantly activated in most colorectal cancers. WNT signaling causes β-catenin to translocate into the nucleus, where it binds and activates the transcription factor TCF. This paper provides an insight into the regulation of β-catenin/TCF-stimulated transcription in colorectal cancer. By two RNAi-based loss-of-function screens, they identified CDK8 in a screen for proteins that both regulate β-catenin activity and cell proliferation in colorectal cancer cell lines. From the results of tissue microarray, 31 out of 50 (62%) cases displayed evidence of CDK8 gene amplification by FISH analysis and these tumors with elevated CDK8 by IHC analysis. These observations indicate that CDK8 is amplified and overexpressed in a substantial fraction of colon cancers. Furthermore, they also showed that CDK8 is required for β-catenin- mediated oncogenic transformation. Depletion of CDK8 reduced β-catenin- dependent transcriptional activity and kinase-dead CDK8 mutant blocked β-catenin-driven oncogenic transformation, these indicating that CDK8 kinase activity is necessary for β-catenin activation. Chromatin immunoprecipitation experiments revealed that CDK8 bound to the MYC proto-oncogene promotera known target for β-catenin/TCF and depletion of CDK8 blocked the ability of β-catenin to bind to the MYC promoter. These observations implicated CDK8 and the mediator complex as a direct regulator of b-catenin-driven transcription. Taken these together, it gives a hint that colorectal tumors with elevated CDK8 levels might make good candidates for novel drug therapies directed at the enzyme.



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