DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation
DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation
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DOI：
10.1038/35050500
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发表时间：
2001-01-01
影响因子：
21.3
通讯作者：
Kimchi, A
中科院分区：
文献类型：
--
作者：
Raveh, T;Droguett, G;Kimchi, A
DAP激酶是一种促凋亡钙调节的丝氨酸/苏氨酸激酶，其表达在人类肿瘤中经常丢失，在这里，我们表明DAP激酶通过激活p19（ARF）/p53依赖性凋亡检查点来抵消癌基因诱导的转化。DAP激酶的异位表达通过以p19（ARF）依赖的方式激活p53抑制原代胚胎成纤维细胞的致癌转化。因此，成纤维细胞发生凋亡，其特征在于半胱天冬酶激活和DNA片段化。响应于c-Myc或E2 F-1，内源性DAP激酶蛋白被上调。此外，内源性DAP激酶的功能或遗传失活降低了p19（ARF）/p53的诱导程度，并削弱了随后对c-Myc或E2 F-1的凋亡反应。这些结果确立了DAP激酶在早期凋亡检查点中的作用，该检查点旨在消除癌症发展期间的癌前细胞。
DAP kinase is a pro-apoptotic calcium-regulated serine/threonine kinase, whose expression is frequently lost in human tumours, Here we show that DAP kinase counteracts oncogene-induced transformation by activating a p19(ARF)/p53-dependent apoptotic checkpoint. Ectopic expression of DAP kinase suppressed oncogenic transformation of primary embryonic fibroblasts by activating p53 in a p19(ARF)-dependent manner. Consequently, the fibroblasts underwent apoptosis, characterized by caspase activation and DNA fragmentation. In response to c-Myc or E2F-1, the endogenous DAP kinase protein was upregulated. Furthermore, functional or genetic inactivation of the endogenous DAP kinase reduced the extent of induction of p19(ARF)/p53 and weakened the subsequent apoptotic responses to c-Myc or E2F-1. These results establish a role for DAP kinase in an early apoptotic checkpoint designed to eliminate pre-malignant cells during cancer development.