PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR
PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR
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DOI：
10.1038/nature05029
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发表时间：
2006-08-17
期刊：
影响因子：
64.8
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
--
作者：
Bernardi, Rosa;Guernah, Ilhem;Pandolfi, Pier Paolo
早幼粒细胞白血病（PML）肿瘤抑制因子的丧失已在几种人类癌症中观察到。PML的肿瘤抑制功能归因于其诱导生长停滞、细胞衰老和凋亡的能力。在这里，我们发现PML是体内新血管生成（新血管形成）的关键抑制剂，在缺血和肿瘤条件下，通过控制蛋白质翻译。我们证明，在缺氧条件下，PML通过抑制哺乳动物雷帕霉素靶蛋白（mTOR），作为缺氧诱导因子1 α (HIF-1 α)合成速率的负调节因子。PML与mTOR物理相互作用，并通过有利于mTOR核积累而负向调节其与小GTPase Rheb的关联。值得注意的是，Pml（-/-）细胞和肿瘤在体外和体内对雷帕霉素的生长抑制都表现出更高的敏感性，并且在小鼠和人类肿瘤中，Pml的缺乏与核糖体蛋白S6的磷酸化和肿瘤血管生成呈负相关。因此，我们的研究结果确定PML是mTOR和新生血管生成的一种新的抑制因子。
Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis ( the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1 alpha (HIF-1 alpha) by repressing mammalian target of rapamycin ( mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml(-/-) cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.