Tetsu O, McCormick F
University of California, San Francisco, School of Medicine, Cancer Research Institute, 94143-0128, USA.
Nature. 1999 Apr 1;398(6726):422-6. doi: 10.1038/18884.
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.
大多数人类结肠癌中都存在腺瘤性息肉病 coli（APC）肿瘤抑制基因的突变。功能性 APC 蛋白的缺失会导致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、胃癌和肝细胞癌中都发现了β-连环蛋白的突变形式。β-连环蛋白的积累会激活对 TCF/LEF 家族转录因子有反应的基因，β-连环蛋白与这些转录因子相互作用。我们在此表明，β-连环蛋白激活细胞周期蛋白 D1 启动子的转录，并且启动子内与 TCF/LEF 结合位点共有序列相关的序列对于激活是必需的。癌蛋白 p21ras 通过启动子内与转录调节因子 Ets 或 CREB 结合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，在结肠癌细胞中表达显性负性形式的 TCF 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。这种显性负性 TCF 导致细胞停滞在细胞周期的 G1 期；通过在巨细胞病毒启动子下表达细胞周期蛋白 D1 可以挽救这种表型。因此，β-连环蛋白的异常水平可能通过导致细胞周期蛋白 D1 的积累而促成肿瘤转化。
