Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia.
Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia.
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发表时间：
1995-09
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通讯作者：
C. Cordon-Cardo
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作者：
C. Cordon-Cardo
肿瘤疾病的特征是细胞生长不协调。细胞增殖在细胞周期中遵循有序的进程，细胞周期由细胞周期蛋白和细胞周期蛋白依赖蛋白激酶组成的蛋白质复合体控制。这些复合体通过磷酸化参与细胞周期转变的关键蛋白来发挥其调节功能，例如视网膜母细胞瘤基因(PRB)编码的产物。细胞周期蛋白和细胞周期蛋白依赖性蛋白激酶的突变和过度表达，主要是细胞周期蛋白D1和CDK4，已被报道并被认为是致癌事件。最近，一类新的负调控分子作为CDK抑制分子被发现。由于它们在细胞周期控制中的隐性性质，以及它们中的一些在人类肿瘤中发生突变的事实，人们认为它们也可能作为肿瘤抑制基因发挥作用。这些蛋白质和复合体的分子网络似乎影响着两个基本的细胞周期调节因子：p53和pRb。这两种核蛋白之间的串扰通路正在被描绘出来，暗示着P53和pRb在细胞周期控制、细胞凋亡和肿瘤进展中的潜在联系。此外，TP53和Rb在原发肿瘤中的高发生率和突变模式使其成为肿瘤抑制基因的原型。此外，检测TP53和Rb突变及其编码产物的表达变化似乎具有临床意义，当在特定癌症中发现时，往往与预后相关。基于这些发现，基因替代疗法这一新兴领域正在开发新的策略。
Neoplastic diseases are characterized by uncoordinated cell growth. Cellular proliferation follows an orderly progression through the cell cycle, which is governed by protein complexes composed of cyclins and cyclin-dependent kinases. These complexes exert their regulatory function by phosphorylation of key proteins involved in cell cycle transitions, such as the product encoded by the retinoblastoma gene (pRB). Mutations and overexpression of cyclins and cyclin-dependent kinases, mainly cyclin D1 and Cdk4, have been reported and proposed to be oncogenic events. More recently, a new family of negative regulators functioning as Cdk-inhibitory molecules has been identified. Because of their recessive nature in cell cycle control and the fact that some of them are mutated in human tumors, it has been suggested that they may also function as tumor suppressor genes. It appears that the molecular networking of these proteins and complexes impact on two fundamental cell cycle regulators: p53 and pRB. Cross-talk pathways between these two nuclear proteins are being delineated, implying potential links between p53 and pRB in cell cycle control, apoptosis, and tumor progression. In addition, the high rate and mutation pattern of TP53 and RB in primary tumors have rendered them prototype tumor suppressor genes. Furthermore, detection of TP53 and RB mutations and altered expression of their encoded products appear to be of clinical significance, often correlating with prognosis, when identified in specific cancers. Based on these findings, new strategies are being developed in the emerging field of gene replacement-therapy.