Minella Alex C, Swanger Jherek, Bryant Eileen, Welcker Markus, Hwang Harry, Clurman Bruce E
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Curr Biol. 2002 Oct 29;12(21):1817-27. doi: 10.1016/s0960-9822(02)01225-3.
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.
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.
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.
细胞周期蛋白E与其催化伙伴细胞周期蛋白依赖性激酶2（cdk2）共同作用，对进入细胞周期的S期起限速作用。癌细胞经常在细胞周期蛋白D-视网膜母细胞瘤蛋白途径中发生突变，导致细胞周期蛋白E-cdk2的不适当激活。尽管细胞周期蛋白E-cdk2活性失调被认为直接促成了这些癌症的肿瘤进展，但细胞周期蛋白E诱导肿瘤形成的机制尚不清楚。
我们研究了原代细胞中细胞周期蛋白E表达失调的后果，发现细胞周期蛋白E引发了一种p53依赖性反应，通过诱导p21Cip1 cdk抑制剂的表达来阻止过量的cdk2活性。p53活性的增加与p14ARF肿瘤抑制因子的表达增加无关。相反，细胞周期蛋白E导致p53丝氨酸15磷酸化增加，这对ATM/ATR家族的抑制剂敏感。当p53或p21cip1失去功能时，过量的细胞周期蛋白E就会具有催化活性，导致S期进程缺陷、倍性增加和基因不稳定。
我们得出结论，p53和p21形成了一个可诱导的屏障，保护细胞免受细胞周期蛋白E-cdk2失调的有害后果。抑制细胞周期蛋白E失调的反应可能是一种针对肿瘤转化的普遍保护机制。因此，在癌细胞中，细胞周期蛋白E失调完全致癌之前，可能需要这种反应的丧失。此外，过量的细胞周期蛋白E和p53缺失的组合可能具有特别的基因毒性，因为细胞无法对过量的细胞周期蛋白E-cdk2活性引起的细胞周期异常做出适当反应。
