Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence
Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence
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DOI：
10.1002/emmm.201200233
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发表时间：
2012-07-01
影响因子：
11.1
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
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作者：
Scaglioni, Pier Paolo;Rabellino, Andrea;Pandolfi, Pier Paolo
原代细胞中致癌K-RAS的表达可诱发癌基因诱导的细胞衰老（OIS），这是一种有效抑制肿瘤发生的生长停滞形式。这种效应主要归因于依赖于p53肿瘤抑制蛋白的转录机制。PML肿瘤抑制因子最初被鉴定为急性早幼粒细胞白血病（APL）的PML-RAR α癌蛋白的组分。PML是一种关键的OIS介质，在体内和体外被致癌K-RAS上调。我们在此证明，即使在p53不存在的情况下，致癌K-RAS通过激活RAS/MEK 1/mTOR/eIF 4 E通路诱导PML蛋白上调。在这些情况下，PML mRNA选择性地与多聚核糖体结合。重要的是，我们发现PML 5'非翻译mRNA区域在介导PML蛋白上调中起关键作用，并且它的存在对于有效的OIS应答是必不可少的。这些发现表明，PML翻译的上调在致癌K-RAS诱导的OIS中起核心作用。因此，选择性翻译起始在肿瘤抑制中起着关键作用，对实体瘤和APL的治疗具有重要的治疗意义。
Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the PML-RARa oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo and in vitro. We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53. Under these circumstances, PML mRNA is selectively associated to polysomes. Importantly, we find that the PML 5' untranslated mRNA region plays a key role in mediating PML protein upregulation and that its presence is essential for an efficient OIS response. These findings demonstrate that upregulation of PML translation plays a central role in oncogenic K-RAS-induced OIS. Thus, selective translation initiation plays a critical role in tumour suppression with important therapeutic implications for the treatment of solid tumours and APL.