PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR Journal Article
| Authors: | Bernardi, R.; Guernah, I.; Jin, D.; Grisendi, S.; Alimonti, A.; Teruya-Feldstein, J.; Cordon-Cardo, C.; Celeste Simon, M.; Rafii, S.; Pandolfi, P. P. |
| Article Title: | PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR |
| Abstract: | 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 1α (HIF-1α) 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. © 2006 Nature Publishing Group. |
| Keywords: | controlled study; protein phosphorylation; unclassified drug; nonhuman; sensitivity analysis; neoplasms; proteins; animal cell; mouse; mammalia; animals; mice; apoptosis; gene expression; protein kinases; neoplasm proteins; animal experiment; animal model; protein; protein binding; cell line, tumor; angiogenesis; neovascularization, pathologic; phosphorylation; transcription factors; nuclear proteins; hypoxia; cancer inhibition; biosynthesis; genetic engineering; ischemia; tumors; mammalian target of rapamycin; tumor suppressor proteins; promyelocytic leukemia; fibroblasts; protein biosynthesis; cell hypoxia; cell nucleus; tumor; hypoxia inducible factor 1alpha; repressor proteins; neuropeptides; rapamycin; sirolimus; diseases; hypoxia-inducible factor 1, alpha subunit; cells; antibiotics; guanosine triphosphatase; monomeric gtp-binding proteins; protein s6; rheb protein; revascularization; ribosomal protein s6; neoplastic conditions; promyelocytic leukaemia (pml) |
| Journal Title: | Nature |
| Volume: | 442 |
| Issue: | 7104 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2006-08-17 |
| Start Page: | 779 |
| End Page: | 785 |
| Language: | English |
| DOI: | 10.1038/nature05029 |
| PUBMED: | 16915281 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 139" - "Export Date: 4 June 2012" - "CODEN: NATUA" - "Source: Scopus" |
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