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首页> 外文期刊>Molecular and Cellular Biology >Induction of p21WAF1/CIP1and Inhibition of Cdk2 Mediated by the Tumor Suppressor p16INK4a
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Induction of p21WAF1/CIP1and Inhibition of Cdk2 Mediated by the Tumor Suppressor p16INK4a

机译：肿瘤抑制因子p16INK4a介导的p21WAF1 / CIP1的诱导和Cdk2的抑制

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The tumor suppressor p16INK4a inhibits cyclin-dependent kinases 4 and 6. This activates the retinoblastoma protein (pRB) and, through incompletely understood events, arrests the cell division cycle. To permit biochemical analysis of the arrest, we generated U2-OS osteogenic sarcoma cell clones in which p16 transcription could be induced. In these clones, binding of p16 to cdk4 and cdk6 abrogated binding of cyclin D1, p27KIP1, and p21WAF1/CIP1. Concomitantly, the total cellular level of p21 increased severalfold via a posttranscriptional mechanism. Most cyclin E-cdk2 complexes associated with p21 and became inactive, expression of cyclin A was curtailed, and DNA synthesis was strongly inhibited. Induction of p21 alone, in a sibling clone, to the level observed during p16 induction substantially reproduced these effects. Overexpression of either cyclin E or A prevented p16 from mediating arrest. We then extended these studies to HCT 116 colorectal carcinoma cells and a p21-null clone derived by homologous recombination. In the parental cells, p16 expression also augmented total cellular and cdk2-bound p21. Moreover, p16 strongly inhibited DNA synthesis in the parental cells but not in the p21-null derivative. These findings indicate that p21-mediated inhibition of cdk2 contributes to the cell cycle arrest imposed by p16 and is a potential point of cooperation between the p16/pRB and p14ARF/p53 tumor suppressor pathways.
机译：肿瘤抑制因子p16 INK4a 抑制细胞周期蛋白依赖性激酶4和6。这激活了成视网膜细胞瘤蛋白（pRB），并通过不完全了解的事件阻止了细胞分裂周期。为了进行逮捕的生化分析，我们生成了可以诱导p16转录的U2-OS成骨肉瘤细胞克隆。在这些克隆中，p16与cdk4和cdk6的结合消除了细胞周期蛋白D1，p27 KIP1 和p21 WAF1 / CIP1 < / sup>。伴随地，通过转录后机制，p21的总细胞水平增加了几倍。大多数与p21相关的细胞周期蛋白E-cdk2复合物变得不活泼，细胞周期蛋白A的表达减少，DNA合成受到强烈抑制。在同胞克隆中，单独诱导p21达到诱导p16的水平基本上重现了这些作用。细胞周期蛋白E或A的过度表达阻止p16介导逮捕。然后，我们将这些研究扩展到HCT 116大肠癌细胞和通过同源重组获得的p21-null克隆。在亲代细胞中，p16表达也增加了细胞总数和cdk2结合的p21。此外，p16强烈抑制了亲代细胞中的DNA合成，但没有抑制p21-null衍生物中的DNA合成。这些发现表明，p21介导的对cdk2的抑制有助于p16强加的细胞周期停滞，并且是p16 / pRB和p14 ARF / p53肿瘤抑制途径之间潜在的合作点。

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