The serine protease inhibitor serpinB2 binds and stabilizes p21 in senescent cells
The serine protease inhibitor serpinB2 binds and stabilizes p21 in senescent cells
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DOI：
10.1242/jcs.204974
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发表时间：
2017-10-01
影响因子：
4
通讯作者：
Lin, Jing-Jer
中科院分区：
文献类型：
--
作者：
Hsieh, Hsi-Hsien;Chen, Ying-Chieh;Lin, Jing-Jer
SerpinB 2是一种丝氨酸蛋白酶抑制剂，也称为纤溶酶原激活物抑制剂2型（派-2）。已充分证明serpinB 2是尿激酶纤溶酶原激活物（uPA）和组织纤溶酶原激活物（tPA）的抑制剂。有趣的是，serpinB 2水平在衰老细胞中增加，因此serpinB 2被认为是衰老生物标志物。在这项研究中，通过模拟衰老细胞中serpinB 2水平的升高，诱导增殖的人成纤维细胞衰老。serpinB 2诱导的衰老与其细胞外功能无关，因为抑制serpinB 2的分泌、外源引入的serpinB 2或未能与其细胞外靶点uPA结合的serpinB 2突变体不影响衰老。我们还发现，serpinB 2是p53的直接下游靶点，通过DNA损伤反应途径激活。值得注意的是，serpinB 2结合并稳定p21以蛋白酶体非依赖性方式介导衰老，表明serpinB 2在衰老中具有直接作用。因此，本研究揭示了serpinB 2通过稳定p21蛋白水平维持衰老的独特机制。
SerpinB2 is a serine protease inhibitor also known as plasminogen activator inhibitor type 2 (PAI-2). It has been well documented that serpinB2 is an inhibitor of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA). Interestingly, serpinB2 levels are increased in senescent cells and serpinB2 is thus considered a senescence biomarker. In this study, by mimicking the elevated levels of serpinB2 in senescent cells, proliferating human fibroblasts were induced into senescence. Senescence induced by serpinB2 did not relate to its extracellular function, as inhibition of serpinB2 secretion, exogenous introduced serpinB2, or a serpinB2 mutant that failed to bind to its extracellular target uPA did not affect senescence. We also showed that serpinB2 is a direct downstream target of p53 that is activated by the DNA damage response pathway. Significantly, serpinB2 bound to and stabilized p21 to mediate senescence in a proteasome-independent manner, indicating that serpinB2 has a direct role in senescence. Thus, this study reveals a unique mechanism by which serpinB2 maintains senescence through stabilization of p21 protein levels.