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HSP70保护Bcl2L12和Bcl2L12A免于N端泛素化介导的蛋白酶体降解
【作者】 杨俊武；
【导师】 顾建新；
【作者基本信息】 复旦大学 ， 生物化学与分子生物学， 2009， 博士
【摘要】 Bcl2l12是一个新发现的Bcl-2家族中的一员,研究表明它对乳腺癌的预后有帮助,同时它还和神经胶质瘤以及大肠癌的发生发展相关。它能够被很多抗肿瘤药物所调控,包括顺铂、卡铂还有拓普替康等等。然而它的转录后修饰以及调控机制还没有被研究过。我的研究发现Bcl2l12和它的转录变异体Bcl2l12A都是核蛋白,它们都通过泛素蛋白酶体系统降解。有趣的是它们的泛素化以及降解不是通过常规的内部赖氨酸残基位点,而是依赖N末端的第一个残基。更进一步的研究发现,在哺乳动物细胞中,Hsp70能够和它们相互作用,保护它们免于被泛素蛋白酶体降解。过表达Bcl2l12A能下调Bcl-2促进细胞凋亡。总而言之,Hsp70能够保护Bcl2l12和Bcl2l12A免于N端泛素化介导的蛋白酶体降解,Bcl2l12A可能是一个潜在的细胞凋亡调节因子。
【Abstract】 BCL2L12, a newly identified member of Bcl-2 family, has been found to be associated with favorable prognosis in breast cancer patients while correlated with tumorigenesis of glioblastoma and colon cancer. It is transcriptionally regulated by many anti-tumor drugs, such as cisplatin, carboplatin and Topotecan. However, the post-translational modification and regulation of this protein has not been studied yet. Here, we report that BCL2L12 and its transcript variant BCL2L12A are nuclear proteins that are degradated through ubiquitin-proteasome system (UPS). Interestingly, the ubiquitinations and degradations of these two proteins are independent of the internal lysine residues but the first N-terminal residues. In addition, we identified HSP70 as an interacting partner of both proteins, which protected them from ubiquitination and degradation in mammalian cells. Furthermore, ectopic expression of BCL2L12A induces apoptosis through down-regulation of Bcl-2. In summary, these data suggest that HSP70 protects BCL2L12 and BCL2L12A from N-terminal ubiquitination-mediated proteasomal degradation, and that BCL2L12A might serve as an apoptosis regulator.