The Pezcoller lecture: cancer cell cycles revisited.
The Pezcoller lecture: cancer cell cycles revisited.
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作者：
C. Sherr
禁用哺乳动物细胞G1期进展关键调控因子的遗传病变存在于大多数人类癌症中。丝裂原依赖性、细胞周期蛋白d依赖性激酶（cdk4和cdk6）磷酸化视网膜母细胞瘤（Rb）肿瘤抑制蛋白，有助于消除其生长抑制作用，并使E2F转录因子激活进入细胞分裂周期DNA合成期(S)所需的基因。e2f应答基因包括细胞周期蛋白E和A，它们与cdk2结合并激活cdk2以促进S期进入和进展。细胞周期蛋白d依赖性激酶在G1期的积累会隔离Cip/Kip家族的cdk2抑制剂，通过促进细胞周期蛋白E-cdk2在G1- s过渡阶段的激活来补充E2F转录程序的作用。“Rb通路”的破坏是由于Rb功能的直接突变失活、细胞周期蛋白d依赖性激酶的过度表达或细胞周期蛋白d依赖性激酶抑制剂p16（INK4a）的缺失。p27（Kip1）水平的降低和cyclin E表达的增加也会发生，并且在许多常见的癌症形式中具有不良的预后意义。ARF肿瘤抑制因子由INK4a-ARF位点的另一个阅读框编码，感知流过Rb通路的“有丝分裂电流”，并由异常生长促进信号诱导。通过拮抗Mdm2 （p53肿瘤抑制因子的负调节因子），ARF触发p53依赖的转录反应，转移早期癌细胞进行生长停滞或凋亡。虽然ARF不会被损伤DNA的信号直接激活，但它的缺失不仅会抑制p53对异常有丝分裂信号的反应，还会使肿瘤细胞对细胞毒性药物和照射产生耐药性。p16- cyclin D-CDK4- Rb和ARF- Mdm2- p53通路的病变在癌症中如此频繁地发生，无论患者年龄或肿瘤类型如何，它们似乎是大多数（如果不是全部）癌细胞生活史的一部分。
Genetic lesions that disable key regulators of G1 phase progression in mammalian cells are present in most human cancers. Mitogen-dependent, cyclin D-dependent kinases (cdk4 and cdk6) phosphorylate the retinoblastoma (Rb) tumor suppressor protein, helping to cancel its growth-inhibitory effects and enabling E2F transcription factors to activate genes required for entry into the DNA synthetic phase (S) of the cell division cycle. Among the E2F-responsive genes are cyclins E and A, which combine with and activate cdk2 to facilitate S phase entry and progression. Accumulation of cyclin D-dependent kinases during G1 phase sequesters cdk2 inhibitors of the Cip/Kip family, complementing the effects of the E2F transcriptional program by facilitating cyclin E-cdk2 activation at the G1-S transition. Disruption of "the Rb pathway" results from direct mutational inactivation of Rb function, by overexpression of cyclin D-dependent kinases, or through loss of p16(INK4a), an inhibitor of the cyclin D-dependent kinases. Reduction in levels of p27(Kip1) and increased expression of cyclin E also occur and carry a poor prognostic significance in many common forms of cancer. The ARF tumor suppressor, encoded by an alternative reading frame of the INK4a-ARF locus, senses "mitogenic current" flowing through the Rb pathway and is induced by abnormal growth promoting signals. By antagonizing Mdm2, a negative regulator of the p53 tumor suppressor, ARF triggers a p53-dependent transcriptional response that diverts incipient cancer cells to undergo growth arrest or apoptosis. Although ARF is not directly activated by signals that damage DNA, its loss not only dampens the p53 response to abnormal mitogenic signals but also renders tumor cells resistant to treatment by cytotoxic drugs and irradiation. Lesions in the p16--cyclin D-CDK4--Rb and ARF--Mdm2--p53 pathways occur so frequently in cancer, regardless of patient age or tumor type, that they appear to be part of the life history of most, if not all, cancer cells.