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

Nature volume 442, pages 779–785 (2006)Cite this article

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.

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Figure 1: Pml -/- mice have accelerated revascularization in response to ischaemia.
Figure 2: Pml controls Hif-1α activity and accumulation rate in hypoxic conditions.
Figure 3: PML regulates mTOR in response to hypoxia.
Figure 4: PML inhibits mTOR activity through physical interaction and co-localization in the nucleus.
Figure 5: Pml -/- tumours have increased angiogenesis, phosphorylation of S6 and sensitivity to rapamycin.

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Acknowledgements

We are grateful to W. Gerald for providing the prostate cancer TMAs. We thank M. Socorro Jiao and M. Drobnjak for help with immunohistochemistry, P. Burgman and S. Carlin for help with hypoxia experiments, B. Carver for help with statistical analysis, L. DiSantis, R. Hobbs and J. Clohessy for critical reading of the manuscript, and all members of the Pandolfi laboratory for comments and discussion. This work was supported by NIH grants to P.P.P.

Author information

Authors and Affiliations

  1. Cancer Biology and Genetics Program,

    Rosa Bernardi, Ilhem Guernah, Silvia Grisendi, Andrea Alimonti & Pier Paolo Pandolfi

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York, 10021, USA

    Rosa Bernardi, Ilhem Guernah, Silvia Grisendi, Andrea Alimonti, Julie Teruya-Feldstein, Carlos Cordon-Cardo & Pier Paolo Pandolfi

  3. Howard Hughes Medical Institute, Department of Genetic Medicine, Division of Hematology-Oncology, Weill–Cornell Medical College, New York, New York, 10021, USA

    David Jin & Shahin Rafii

  4. Howard Hughes Medical Institute, Department of Cell & Developmental Biology and Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania, 19104, USA

    M. Celeste Simon

  5. Developmental Biology and Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center,

    M. Celeste Simon

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  1. Rosa Bernardi
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Correspondence to Pier Paolo Pandolfi.

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Supplementary information

Supplementary Figure 1

High Hif-1α levels and Hif-1α transcriptional activity in Pml-/- cells in hypoxia. (PDF 448 kb)

Supplementary Figure 2

High Hif-1α levels in human cell lines stably transfected with PML. (PDF 442 kb)

Supplementary Figure 3

High S6K phosphorylation in Pml-/- cells in hypoxia and serum starvation. (PDF 526 kb)

Supplementary Figure 4

Inhibition of mTOR activity by PML overexpression. (PDF 1077 kb)

Supplementary Figure 5

Characterization of wt and Pml-/- transformed cells in vitro and in vivo. (PDF 411 kb)

Supplementary Notes

This file contains Supplementary Methods (Cell culture, mice and reagents; hind-limb ischemia surgery; plasmids, cell transfections and transactivation assays; real-time PCR; western blotting; TMA analysis; and statistical evaluation), Supplementary Figure Legends and additional references. (DOC 51 kb)

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Bernardi, R., Guernah, I., Jin, D. et al. PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR. Nature 442, 779–785 (2006). https://doi.org/10.1038/nature05029

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