Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity.
Cystatin C as a p53-inducible apoptotic mediator that regulates cathepsin L activity.
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DOI：
10.1111/cas.12881
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发表时间：
2016-03
期刊：
影响因子：
5.7
通讯作者：
Matsuda K
中科院分区：
文献类型：
--
作者：
Mori J;Tanikawa C;Funauchi Y;Lo PH;Nakamura Y;Matsuda K
在各种细胞应激反应中，p53被激活并通过其靶基因的转录调节来抑制恶性转化。然而，p53下游通路的全貌仍有待阐明。在这里，我们确定了cystatin C，组织蛋白酶的主要抑制剂，作为一种新的p53靶点。作为对DNA损伤的反应，激活的p53通过第一内含子中的p53结合序列诱导胱抑素C表达。我们发现，组织蛋白酶L活性在HCT 116 p53 +/+细胞中阿霉素处理后降低，但在HCT 116 p53 −/−细胞中没有。我们还发现，敲低半胱氨酸蛋白酶抑制剂C减少阿霉素诱导的caspase-3活化。在p53突变的乳腺癌细胞中，半胱氨酸蛋白酶抑制剂C表达显着下调，并且半胱氨酸蛋白酶抑制剂C表达下降与乳腺癌预后不良相关。我们的研究结果揭示了p53-cystatin C通路在人类肿瘤发生中的重要作用。
In response to various cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes. However, the full picture of the p53 downstream pathway still remains to be elucidated. Here we identified cystatin C, a major inhibitor of cathepsins, as a novel p53 target. In response to DNA damage, activated p53 induced cystatin C expression through p53 binding sequence in the first intron. We showed that cathepsin L activity was decreased in HCT116 p53 +/+ cells after adriamycin treatment, but not in HCT116 p53 −/− cells. We also found that knockdown of cystatin C reduced adriamycin‐induced caspase‐3 activation. Cystatin C expression was significantly downregulated in breast cancer cells with p53 mutations, and decreased cystatin C expression was associated with poor prognosis of breast cancer. Our findings revealed an important role of the p53–cystatin C pathway in human carcinogenesis.