p53 and p21 form an inducible barrier that protects cells against cyclin E-cdk2 deregulation
p53 and p21 form an inducible barrier that protects cells against cyclin E-cdk2 deregulation
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DOI：
10.1016/s0960-9822(02)01225-3
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发表时间：
2002-10-29
期刊：
影响因子：
9.2
通讯作者：
Clurman, BE
中科院分区：
文献类型：
--
作者：
Minella, AC;Swanger, J;Clurman, BE
背景：细胞周期蛋白E与其催化伙伴CDK2一起，是进入细胞周期S时相的限速因子。癌细胞经常在细胞周期蛋白D-视网膜母细胞瘤蛋白通路中含有突变，从而导致细胞周期蛋白E-CDK2的不适当激活。结果：我们研究了原代细胞中细胞周期蛋白E表达异常的后果，发现细胞周期蛋白E通过诱导p21Cip1 cdk抑制因子的表达，启动了一种p53依赖的反应，从而阻止了细胞周期蛋白CDK2的过度活性。P53活性升高与p14ARF抑癌基因表达增强无关。相反，细胞周期蛋白E导致对ATM/ATR家族抑制剂敏感的P53丝氨酸15磷酸化增加。当p53或p21cip1失去功能时，过量的细胞周期蛋白E变得催化活性，导致S期进程缺陷、倍体增加和遗传不稳定性。结论：我们得出结论：p53和p21形成一种诱导屏障，保护细胞免受细胞周期蛋白E-CDK2去调控的有害后果。抑制细胞周期蛋白E去调控的反应可能是一种防止肿瘤转化的一般保护机制。因此，在去调控的细胞周期蛋白E在癌细胞中完全致癌之前，可能需要失去这种反应。此外，过量的细胞周期蛋白E和p53丢失的组合可能具有特别的遗传毒性，因为细胞不能适当地对由细胞周期蛋白E-CDK2过度活性引起的细胞周期异常做出反应。
Background: Cyclin E, in conjunction with its catalytic partner cdk2, is rate limiting for entry into the S phase of the cell cycle. Cancer cells frequently contain mutations within the cyclin D-Retinoblastoma protein pathway that lead to inappropriate cyclin E-cdk2 activation. Although deregulated cyclin E-cdk2 activity is believed to directly contribute to the neoplastic progression of these cancers, the mechanism of cyclin E-induced neoplasia is unknown.Results: We studied the consequences of deregulated cyclin E expression in primary cells and found that cyclin E initiated a p53-dependent response that prevented excess cdk2 activity by inducing expression of the p21Cip1 cdk inhibitor. The increased p53 activity was not associated with increased expression of the p14ARF tumor suppressor. Instead, cyclin E led to increased p53 serine15 phosphorylation that was sensitive to inhibitors of the ATM/ATR family. When either p53 or p21cip1 was rendered nonfunctional, then the excess cyclin E became catalytically active and caused defects in S phase progression, increased ploidy, and genetic instability.Conclusions: We conclude that p53 and p21 form an inducible barrier that protects cells against the deleterious consequences of cyclin E-cdk2 deregulation. A response that restrains cyclin E deregulation is likely to be a general protective mechanism against neoplastic transformation. Loss of this response may thus be required before deregulated cyclin E can become fully oncogenic in cancer cells. Furthermore, the combination of excess cyclin E and p53 loss may be particularly genotoxic, because cells cannot appropriately respond to the cell cycle anomalies caused by excess cyclin E-cdk2 activity.