Werner syndrome protein limits MYC-induced cellular senescence
Werner syndrome protein limits MYC-induced cellular senescence
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DOI：
10.1101/gad.1100303
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发表时间：
2003-07-01
影响因子：
10.5
通讯作者：
Mormat, RJ
中科院分区：
文献类型：
--
作者：
Grandori, C;Wu, KJ;Mormat, RJ
MYC癌蛋白是协调细胞生长和分裂的转录因子。MYC过表达加剧基因组不稳定性并使细胞对凋亡刺激物敏感。在这里，我们证明，MYC直接刺激人类沃纳综合征基因，WRN，它编码一个保守的RecQ解旋酶的转录。WRN中的功能丧失突变导致基因组不稳定、癌症风险升高和细胞过早衰老。MYC在WRN综合征成纤维细胞中的过表达或在对照成纤维细胞的WRN耗尽后导致不能被hTERT表达抑制的快速细胞衰老。我们认为MYC上调WRN可能通过阻止细胞衰老促进MYC驱动的肿瘤发生。
The MYC oncoprotein is a transcription factor that coordinates cell growth and division. MYC overexpression exacerbates genomic instability and sensitizes cells to apoptotic stimuli. Here we demonstrate that MYC directly stimulates transcription of the human Werner syndrome gene, WRN, which encodes a conserved RecQ helicase. Loss-of-function mutations in WRN lead to genomic instability, an elevated cancer risk, and premature cellular senescence. The overexpression of MYC in WRN syndrome fibroblasts or after WRN depletion from control fibroblasts led to rapid cellular senescence that could not be suppressed by hTERT expression. We propose that WRN up-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence.