E2F1抑制β-连环蛋白转录，并受到pRB和CDK8的拮抗。
E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8.
作者信息
Morris Erick J, Ji Jun-Yuan, Yang Fajun, Di Stefano Luisa, Herr Anabel, Moon Nam-Sung, Kwon Eun-Jeong, Haigis Kevin M, Näär Anders M, Dyson Nicholas J
机构信息
Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA.
出版信息
Nature. 2008 Sep 25;455(7212):552-6. doi: 10.1038/nature07310. Epub 2008 Sep 14.
The E2F1 transcription factor can promote proliferation or apoptosis when activated, and is a key downstream target of the retinoblastoma tumour suppressor protein (pRB). Here we show that E2F1 is a potent and specific inhibitor of beta-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumours, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Thus, by retaining RB1 and amplifying CDK8, colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.
E2F1转录因子在被激活时可促进增殖或诱导凋亡，是视网膜母细胞瘤抑癌蛋白（pRB）的关键下游靶点。我们在此表明，E2F1是β-连环蛋白/T细胞因子（TCF）依赖性转录的强效特异性抑制剂，且该功能促成了E2F1诱导的凋亡。E2F1失调以一种不依赖腺瘤性息肉病大肠杆菌（APC）/糖原合酶激酶-3（GSK3）的方式抑制β-连环蛋白活性，降低包括c-MYC在内的关键β-连环蛋白靶点的表达。这种相互作用解释了为何依赖β-连环蛋白转录进行异常增殖的结直肠癌会保持RB1完整。值得注意的是，E2F1活性也受到细胞周期蛋白依赖性激酶8（CDK8，一种结直肠癌癌蛋白）的抑制。CDK8水平升高可保护β-连环蛋白/TCF依赖性转录免受E2F1的抑制。因此，通过保留RB1并增强CDK8，结直肠肿瘤细胞选择了共同抑制E2F1并增强β-连环蛋白活性的条件。
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