Proteolytic cleavage of human p53 by calpain: A potential regulator of protein stability
Proteolytic cleavage of human p53 by calpain: A potential regulator of protein stability
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DOI：
10.1128/mcb.17.1.460
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发表时间：
1997-01-01
影响因子：
5.3
通讯作者：
Vousden, KH
中科院分区：
文献类型：
--
作者：
Kubbutat, MHG;Vousden, KH
p53肿瘤抑制蛋白在细胞中响应于DNA损伤而被激活，并且通过诱导细胞周期停滞或凋亡来防止维持遗传损伤的细胞的复制。p53的激活伴随着蛋白质的稳定，导致在细胞内积累到高水平。p53通常在泛素化后通过蛋白酶体降解，尽管在正常细胞中调节这种蛋白水解的机制以及p53蛋白在DNA损伤后如何变得稳定还不清楚。在这里，我们表明，p53也可以是一个底物的钙激活的中性蛋白酶，钙蛋白酶切割，和钙蛋白酶切割的优先网站内存在的p53蛋白的N末端。用钙蛋白酶抑制剂处理表达野生型p53的细胞导致p53蛋白的稳定。相比之下，人乳头瘤病毒E6蛋白介导的体外或体内降解不受钙蛋白酶抑制剂的影响，这表明稳定性不是由蛋白酶体的抑制引起的。这些结果表明，钙蛋白酶切割在调节p53稳定性中起作用。
The p53 tumor suppressor protein is activated in cells in response to DNA damage and prevents the replication of cells sustaining genetic damage bg inducing a cell cycle arrest or apoptosis. Activation of p53 is accompanied by stabilization of the protein, resulting in accumulation to high levels within the cell. p53 is normally degraded through the proteasome following ubiquitination, although the mechanisms which regulate this proteolysis in normal cells and how the p53 protein becomes stabilized following DNA damage are not well understood. We show here that p53 can also be a substrate for cleavage by the calcium-activated neutral protease, calpain, and that a preferential site for calpain cleavage exists within the N terminus of the p53 protein. Treatment of cells expressing, wild-type p53 with an inhibitor of calpain resulted in the stabilization of the p53 protein. By contrast, in vitro or in vivo degradation mediated by human papillomavirus E6 protein was unaffected by the calpain inhibitor, indicating that the stabilization did not result from inhibition of the proteasome. These results suggest that calpain cleavage plays a role in regulating p53 stability.