P34 CDC2 IN APOPTOSIS AND GENETIC INSTABILITY OF CANCERS

细胞毒性抗癌药的成功与否取决于 肿瘤细胞激活基因编程的能力 自主性细胞死亡的过程，称为细胞凋亡，以响应 诱导DNA损伤。大多数人类癌症都隐藏在 导致细胞凋亡易感性降低的基因改变 以及由此产生的对多种抗癌剂的交叉耐药性。这个 P53抑癌基因是诱导肿瘤发生的关键成分 在DNA损伤诱导的细胞凋亡中，经常被灭活 人类癌症。高效抗肿瘤药物的研究进展 对抗P53缺陷型人类癌症的策略取决于 阐明DNA的基本分子机制 损伤诱导细胞凋亡。细胞对DNA损伤的反应 涉及细胞周期进程在G2/M期的短暂停滞 通过使p34cdc2激酶失活而转变，从而允许时间 用于DNA修复。在存在的情况下未能抑制p34cdc2 受损或未复制的DNA导致致命的有丝分裂表型 (称为有丝分裂灾难)，表现出让人想起 细胞凋亡。初步研究表明：(I)DNA损伤 诱导细胞凋亡需要激活p34cdc2激酶，以及(Ii) P34cdc2激酶在细胞凋亡过程中的激活依赖于 与进化有关的进化保守的半胱氨酸蛋白酶家族 白介素1β转换酶(ICE)和 CPP32beta(YAMA/阿波班)。这些观察结果表明， ICE/CPP32Beta相关酶和p32cdc2激酶的活性。 这些研究旨在为 抗P53基因实验性治疗策略的研究进展 基于调节特定生化和蛋白质的缺陷性癌症 细胞周期调控的细胞凋亡决定因素。

The success of cytotoxic anticancer agents is determined by the ability of the tumor cell to activate a genetically programmed process of autonomous cell death, termed apoptosis, in response to induced DNA damage. The majority of human cancers harbor genetic alterations that dictate a decreased susceptibility to apoptosis and consequent cross-resistance to multiple anticancer agents. The p53 tumor suppressor gene, a critical component for the induction of DNA damage induced apoptosis, is frequently inactivated in human cancers. The development of effective antineoplastic strategies against p53 deficient human cancers is contingent upon an elucidation of the fundamental molecular mechanisms of DNA damage induced apoptosis. The cellular response to DNA damage involves the transient arrest of cell cycle progression at the G2/M transition by inactivation of p34 cdc2 kinase, thereby allowing time for DNA repair. Failure to inhibit p34cdc2 in the presence of damaged or unreplicated DNA results in lethal mitotic phenotypes (termed "mitotic catastrophes") that exhibit features reminiscent of apoptosis. Preliminary studies suggest that (I) DNA damage induced apoptosis requires activation of p34cdc2 kinase, and (ii) activation of p34cdc2 kinase during apoptosis is dependent upon a family of evolutionarily conserved cysteine proteases related to interleukin-1beta converting enzyme (ICE) and CPP32beta(Yama/Apopain). These observations suggest that the activity of ICE/CPP32Beta-related proteases and p32cdc2 kinase. These studies are designed to provide a foundation for the development of experimental therapeutic strategies against p53- deficient cancers based upon modulating specific biochemical and cell cycle regulatory determinants of apoptosis.