Caspase-dependent BRCA1 cleavage facilitates chemotherapy-induced apoptosis
Caspase-dependent BRCA1 cleavage facilitates chemotherapy-induced apoptosis
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DOI：
10.1007/s10495-007-0167-4
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发表时间：
2008-02-01
期刊：
影响因子：
7.2
通讯作者：
Venezia, Nicole Dalla
中科院分区：
文献类型：
--
作者：
Dizin, Eva;Ray, Hind;Venezia, Nicole Dalla
BRCA 1作为一种肿瘤抑制基因，在很大一部分乳腺癌和卵巢癌家族中发现了该基因的生殖系突变。BRCA 1蛋白参与了多种细胞过程，如转录调控、DNA损伤信号的DNA应答、细胞周期控制和细胞凋亡。细胞凋亡在放疗和化疗诱导的细胞毒性中起关键作用，其损伤有助于对肿瘤治疗的抵抗。为了阐明BRCA 1在细胞凋亡中的作用，我们研究了表达生理水平BRCA 1蛋白的细胞对化疗药物的反应。我们发现，化疗诱导的细胞凋亡导致半胱天冬酶介导的BRCA 1裂解。然后我们发现BRCA 1-p90切割产物主要定位于细胞质中。最后，我们证明了影响BRCT串联重复序列的癌症相关突变会破坏其促凋亡功能。这里提供的数据提供了新的见解内源性BRCA 1作为介导细胞凋亡的作用，并显示BRCA 1的功能作为一个分子决定因素的范围内的细胞毒性化疗药物的反应。
BRCA1 acts as a tumor suppressor gene, and germ-line mutations in this gene are found in a large proportion of families with breast and ovarian cancers. The BRCA1 protein has been implicated in several cellular processes, such as transcription regulation, DNA responses to DNA damage signals, cell cycle control, and apoptosis. Apoptosis plays a critical role in radiation- and chemotherapy-induced cytotoxicity, and its impairment contributes to resistance to tumor treatments. In an attempt to elucidate the role of BRCA1 in apoptosis, we examined the response to chemotherapeutic drugs of cells expressing physiological levels of BRCA1 protein. We showed that chemotherapy-induced apoptosis leads to a caspase-mediated cleavage of BRCA1. We then showed that the BRCA1-p90 cleavage product is mainly localized in the cytoplasm. Finally, we demonstrated that cancer-associated mutations affecting the BRCT tandem repeat abolish its pro-apoptotic function. The data presented here provide new insight into the role of endogenous BRCA1 as a mediator of apoptosis and show that BRCA1 functions as a molecular determinant of response to a range of cytotoxic chemotherapeutic agents.