WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway.
WNT16B is a new marker of cellular senescence that regulates p53 activity and the phosphoinositide 3-kinase/AKT pathway.
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DOI：
10.1158/0008-5472.can-09-1016
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Pedeux R
中科院分区：
文献类型：
--
作者：
Binet R;Ythier D;Robles AI;Collado M;Larrieu D;Fonti C;Brambilla E;Brambilla C;Serrano M;Harris CC;Pedeux R
衰老是一种受多种刺激诱导的肿瘤抑制机制，包括致癌信号和端粒缩短，并受p53/p21WAF1信号通路控制。最近，分泌因子的关键作用已经出现，这表明细胞外信号对于衰老的开始和维持是必要的。相反，衰老细胞分泌的因子可能会促进肿瘤的生长。通过使用表达谱技术，我们寻找在经历复制衰老的成纤维细胞中过度表达的分泌因子。我们鉴定了WNT16B，它是WNT分泌蛋白家族的成员。我们发现WNT16B在经历应激诱导的早衰和癌基因诱导的衰老的细胞中过表达，在MRC5细胞系和KRasV12诱导的小鼠体内衰老模型中都是如此。通过小干扰RNA实验，我们观察到P53和WNT16B都是复制衰老开始所必需的。WNT16B的表达是p21WAF1完全转录激活所必需的。此外，WNT16B还调节磷脂酰肌醇3-激酶(PI3K)/AKT通路的激活。总体而言，我们确定WNT16B是一种新的衰老标记，它调节P53活性和PI3K/AKT途径，是复制衰老开始所必需的。[癌症资源2009；69：9183-91]
Senescence is a tumor suppression mechanism that is induced by several stimuli, including oncogenic signaling and telomere shortening, and controlled by the p53/p21WAF1 signaling pathway. Recently, a critical role for secreted factors has emerged, suggesting that extracellular signals are necessary for the onset and maintenance of senescence. Conversely, factors secreted by senescent cells may promote tumor growth. By using expression profiling techniques, we searched for secreted factors that were overexpressed in fibroblasts undergoing replicative senescence. We identified WNT16B, a member of the WNT family of secreted proteins. We found that WNT16B is overexpressed in cells undergoing stress-induced premature senescence and oncogene-induced senescence in both MRC5 cell line and the in vivo murine model of KRasV12–induced senescence. By small interfering RNA experiments, we observed that both p53 and WNT16B are necessary for the onset of replicative senescence. WNT16B expression is required for the full transcriptional activation of p21WAF1. Moreover, WNT16B regulates activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overall, we identified WNT16B as a new marker of senescence that regulates p53 activity and the PI3K/AKT pathway and is necessary for the onset of replicative senescence. [Cancer Res 2009;69:9183–91]