Plasminogen activator inhibitor 1 - insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence
Plasminogen activator inhibitor 1 - insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence
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DOI：
10.1073/pnas.1120437109
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发表时间：
2012-07-24
影响因子：
11.1
通讯作者：
Shiio, Yuzuru
中科院分区：
文献类型：
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作者：
Elzi, David J.;Lai, Yanlai;Shiio, Yuzuru
人们普遍认为细胞衰老在肿瘤抑制中起关键作用，但调控衰老的分子途径尚不完全清楚。通过使用分泌组蛋白组学方法，我们发现胰岛素样生长因子结合蛋白3 （IGFBP3）是化疗药物治疗后乳腺癌衰老的分泌介质。IGFBP3的衰老诱导活性被组织型纤溶酶原激活物介导的蛋白水解所抑制，而这种蛋白水解被另一种分泌的衰老介质纤溶酶原激活物抑制剂1 （PAI-1）所抵消。我们证明IGFBP3是pai -1诱导衰老的关键下游靶点。这些结果表明细胞外级联分泌蛋白在细胞衰老调节中的作用。
Cellular senescence is widely believed to play a key role in tumor suppression, but the molecular pathways that regulate senescence are only incompletely understood. By using a secretome proteomics approach, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment. The senescence-inducing activity of IGFBP3 is inhibited by tissue-type plasminogen activator-mediated proteolysis, which is counteracted by plasminogen activator inhibitor 1 (PAI-1), another secreted mediator of senescence. We demonstrate that IGFBP3 is a critical downstream target of PAI-1-induced senescence. These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence.