Zhang Y W, Morita I, Ikeda M, Ma K W, Murota S
Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, 113-8549 Tokyo Japan.
Oncogene. 2001 Jul 12;20(31):4138-49. doi: 10.1038/sj.onc.1204563.
Many lines of evidence indicate that connexin genes expressing gap junction (GJ) proteins inhibit tumor cell proliferation. However, the precise molecular mechanisms remain unclear. In this study, we show that overexpression of connexin43 (Cx43) suppressed proliferation of human osteosarcoma U2OS cells through inhibition of the cell cycle transition from G1 to S phase. This inhibition was attributed to a significant accumulation of the hypophosphorylated retinoblastoma (Rb) protein, which was causally related to decreases in the kinase activities of cyclin-dependent kinases (CDKs) 2 and 4. Enforced Cx43 expression markedly increased the level of the CDK inhibitor p27. This increase resulted from an increased synthesis and a reduced degradation of the p27 proteins, but not influence of the p27 mRNA. Moreover, we show that the Cx43-modulated GJ function was the main contributor to the elevation in p27 levels, in which cAMP was involved. These data suggest that Cx43 appears to inhibit proliferation of U2OS cells by increasing the levels of p27 proteins via post-transcriptional regulatory mechanisms.
许多证据表明，表达间隙连接（GJ）蛋白的连接蛋白基因可抑制肿瘤细胞增殖。然而，确切的分子机制仍不清楚。在本研究中，我们发现连接蛋白43（Cx43）的过表达通过抑制细胞周期从G1期向S期的转变来抑制人骨肉瘤U2OS细胞的增殖。这种抑制作用归因于低磷酸化视网膜母细胞瘤（Rb）蛋白的显著积累，这与细胞周期蛋白依赖性激酶（CDK）2和4激酶活性的降低有因果关系。强制表达Cx43可显著提高CDK抑制剂p27的水平。这种增加是由于p27蛋白合成增加和降解减少所致，而非p27 mRNA的影响。此外，我们表明Cx43调节的GJ功能是p27水平升高的主要原因，其中涉及cAMP。这些数据表明，Cx43似乎通过转录后调控机制增加p27蛋白水平来抑制U2OS细胞的增殖。
