Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
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作者：
O. Tetsu;F. McCormick
大肠腺瘤性息肉病（APC）肿瘤抑制基因的突变发生在大多数人类结肠癌中。功能性APC蛋白的丧失导致β-连环蛋白的积累。在保留野生型APC基因的结肠癌中，以及在黑色素瘤、髓母细胞瘤、前列腺癌、胃癌和肝细胞癌中发现了β-连环蛋白的突变形式。β-连环蛋白的积累激活对TCF/LEF家族的转录因子有反应的基因，β-连环蛋白与TCF/LEF家族的转录因子相互作用。在这里，我们表明，β-连环蛋白激活转录从细胞周期蛋白D1启动子，并在启动子内的序列是有关的共识TCF/LEF结合位点是必要的激活。癌蛋白p21 ras通过启动子内结合转录调节因子Ets或CREB的位点进一步激活细胞周期蛋白D1基因的转录。表达突变型β-连环蛋白的细胞组成性地产生高水平的细胞周期蛋白D1信使RNA和蛋白质。此外，在结肠癌细胞中TCF的显性阴性形式的表达强烈抑制细胞周期蛋白D1的表达，而不影响细胞周期蛋白D2、细胞周期蛋白E或细胞周期蛋白依赖性激酶2、4或6的表达。这种显性阴性TCF导致细胞停滞在细胞周期的G1期;这种表型可以通过在巨细胞病毒启动子下表达细胞周期蛋白D1来挽救。因此，β-连环蛋白的异常水平可能通过引起细胞周期蛋白D1的积累而导致肿瘤转化。
Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.