Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
EMBO Mol Med. 2012 Jul;4(7):594-602. doi: 10.1002/emmm.201200233. Epub 2012 Mar 21.
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-RARα 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.
致癌性 K-RAS 在原代细胞中的表达会引发致癌基因诱导的细胞衰老（OIS），这是一种强烈抑制肿瘤发生的生长停滞形式。这种效应在很大程度上归因于依赖于 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-RARα 致癌蛋白的一个组成部分。PML 是 OIS 的关键介质，在体内和体外都被致癌性 K-RAS 上调。我们在这里证明，即使在没有 p53 的情况下，致癌性 K-RAS 通过激活 RAS/MEK1/mTOR/eIF4E 途径也会诱导 PML 蛋白上调。在这些情况下，PML mRNA 选择性地与多核糖体结合。重要的是，我们发现 PML 5'非翻译 mRNA 区域在介导 PML 蛋白上调中起着关键作用，其存在对于有效的 OIS 反应是必不可少的。这些发现表明，PML 翻译的上调在致癌性 K-RAS 诱导的 OIS 中起着核心作用。因此，选择性翻译起始在肿瘤抑制中起着关键作用，这对治疗实体瘤和 APL 具有重要的治疗意义。
