PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR

Rosa Bernardi, Ilhem Guernah, David Jin, Silvia Grisendi, Andrea Alimonti, Julie Teruya-Feldstein, Carlos Cordon-Cardo, M. Celeste Simon, Shahin Rafii, Pier Paolo Pandolfi

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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.

Original languageEnglish
Pages (from-to)779-785
Number of pages7
JournalNature
Volume442
Issue number7104
DOIs
Publication statusPublished - Aug 17 2006

ASJC Scopus subject areas

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    Bernardi, R., Guernah, I., Jin, D., Grisendi, S., Alimonti, A., Teruya-Feldstein, J., Cordon-Cardo, C., Celeste Simon, M., Rafii, S., & Pandolfi, P. P. (2006). PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR. Nature, 442(7104), 779-785. https://doi.org/10.1038/nature05029