P34 CDC2 IN APOPTOSIS AND GENETIC INSTABILITY OF CANCERS

细胞毒性抗癌剂的成功取决于 肿瘤细胞激活基因程序的能力 一种自发性细胞死亡的过程，称为凋亡， 导致DNA损伤。 大多数的人类癌症 基因改变导致细胞凋亡的易感性降低 以及随之而来的对多种抗癌剂的交叉耐药性。 的 p53肿瘤抑制基因，诱导的关键成分 DNA损伤诱导的细胞凋亡，经常被灭活， 人类癌症 发展有效的 针对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p34 cdc 2激酶的失活， for DNA修复. 在存在以下物质的情况下不能抑制p34 cdc 2 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”），其表现出的特征让人想起 凋亡 初步研究表明：（1）DNA损伤 诱导的细胞凋亡需要p34 cdc 2激酶的激活，和（ii） 在凋亡过程中p34 cdc 2激酶的激活依赖于 进化上保守的半胱氨酸蛋白酶家族， 白细胞介素-1 β转化酶（ICE）和 CPP32 β（Yama/Apopain）。 这些观察表明， ICE/CPP 32 β相关蛋白酶和p32 cdc 2激酶的活性。 这些研究旨在为 针对p53的实验性治疗策略的发展- 基于调节特定的生物化学和 细胞凋亡的细胞周期调控决定因素。

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.