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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.

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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.

References

  1. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996)

    CAS  Article  Google Scholar 

  2. Ferrara, N. Vascular endothelial growth factor: basic science and clinical progress. Endocr. Rev. 25, 581–611 (2004)

    CAS  Article  Google Scholar 

  3. Semenza, G. L. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol. Med. 8, S62–S67 (2002)

    CAS  Article  Google Scholar 

  4. de The, H. et al. The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991)

    CAS  Article  Google Scholar 

  5. Goddard, A. D., Borrow, J., Freemont, P. S. & Solomon, E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 254, 1371–1374 (1991)

    ADS  CAS  Article  Google Scholar 

  6. Kakizuka, A. et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML. Cell 66, 663–674 (1991)

    CAS  Article  Google Scholar 

  7. Pandolfi, P. P. et al. Structure and origin of the acute promyelocytic leukemia myl/RARα cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 6, 1285–1292 (1991)

    CAS  PubMed  Google Scholar 

  8. Rego, E. M. et al. Role of promyelocytic leukemia (PML) protein in tumor suppression. J. Exp. Med. 193, 521–529 (2001)

    CAS  Article  Google Scholar 

  9. Salomoni, P. & Pandolfi, P. P. The role of PML in tumor suppression. Cell 108, 165–170 (2002)

    CAS  Article  Google Scholar 

  10. Wang, Z. G. et al. PML is essential for multiple apoptotic pathways. Nature Genet. 20, 266–272 (1998)

    CAS  Article  Google Scholar 

  11. Wang, Z. G. et al. Role of PML in cell growth and the retinoic acid pathway. Science 279, 1547–1551 (1998)

    ADS  CAS  Article  Google Scholar 

  12. Trotman, L. C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006)

    ADS  CAS  Article  Google Scholar 

  13. Koken, M. H. et al. The PML growth-suppressor has an altered expression in human oncogenesis. Oncogene 10, 1315–1324 (1995)

    CAS  PubMed  Google Scholar 

  14. Gambacorta, M. et al. Heterogeneous nuclear expression of the promyelocytic leukemia (PML) protein in normal and neoplastic human tissues. Am. J. Pathol. 149, 2023–2035 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang, P. et al. Lack of expression for the suppressor PML in human small cell lung carcinoma. Int. J. Cancer 85, 599–605 (2000)

    CAS  Article  Google Scholar 

  16. Gurrieri, C. et al. Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J. Natl Cancer Inst. 96, 269–279 (2004)

    CAS  Article  Google Scholar 

  17. Lin, H. K., Bergmann, S. & Pandolfi, P. P. Cytoplasmic PML function in TGF-β signalling. Nature 431, 205–211 (2004)

    ADS  CAS  Article  Google Scholar 

  18. Takahashi, Y., Lallemand-Breitenbach, V., Zhu, J. & de The, H. PML nuclear bodies and apoptosis. Oncogene 23, 2819–2824 (2004)

    CAS  Article  Google Scholar 

  19. Marti, H. H. & Risau, W. Angiogenesis in ischemic disease. Thromb. Haemost. 82 (suppl. 1), 44–52 (1999)

    PubMed  Google Scholar 

  20. Rafii, S. & Lyden, D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nature Med. 9, 702–712 (2003)

    CAS  Article  Google Scholar 

  21. Rabbany, S. Y., Heissig, B., Hattori, K. & Rafii, S. Molecular pathways regulating mobilization of marrow-derived stem cells for tissue revascularization. Trends Mol. Med. 9, 109–117 (2003)

    CAS  Article  Google Scholar 

  22. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001)

    CAS  Article  Google Scholar 

  23. Amano, K. et al. Mechanism for IL-1β-mediated neovascularization unmasked by IL-1β knock-out mice. J. Mol. Cell. Cardiol. 36, 469–480 (2004)

    CAS  Article  Google Scholar 

  24. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003)

    CAS  Article  Google Scholar 

  25. Kaelin, W. G. Jr. How oxygen makes its presence felt. Genes Dev. 16, 1441–1445 (2002)

    CAS  Article  Google Scholar 

  26. Brahimi-Horn, C. & Pouyssegur, J. When hypoxia signalling meets the ubiquitin-proteasomal pathway, new targets for cancer therapy. Crit. Rev. Oncol. Hematol. 53, 115–123 (2005)

    Article  Google Scholar 

  27. Arsham, A. M., Howell, J. J. & Simon, M. C. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J. Biol. Chem. 278, 29655–29660 (2003)

    CAS  Article  Google Scholar 

  28. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004)

    CAS  Article  Google Scholar 

  29. Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521–531 (2006)

    Article  Google Scholar 

  30. Dufner, A. & Thomas, G. Ribosomal S6 kinase signaling and the control of translation. Exp. Cell Res. 253, 100–109 (1999)

    CAS  Article  Google Scholar 

  31. Harrington, L. S., Findlay, G. M. & Lamb, R. F. Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem. Sci. 30, 35–42 (2005)

    CAS  Article  Google Scholar 

  32. Martin, D. E. & Hall, M. N. The expanding TOR signaling network. Curr. Opin. Cell Biol. 17, 158–166 (2005)

    CAS  Article  Google Scholar 

  33. Long, X., Ortiz-Vega, S. & Avruch, J. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J. Biol. Chem. 280, 23433–23436 (2005)

    CAS  Article  Google Scholar 

  34. Kim, J. E. & Chen, J. Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Proc. Natl Acad. Sci. USA 97, 14340–14345 (2000)

    ADS  CAS  Article  Google Scholar 

  35. Park, I. H., Bachmann, R., Shirazi, H. & Chen, J. Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J. Biol. Chem. 277, 31423–31429 (2002)

    CAS  Article  Google Scholar 

  36. Paglin, S. et al. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res. 65, 11061–11070 (2005)

    CAS  Article  Google Scholar 

  37. Jensen, K., Shiels, C. & Freemont, P. S. PML protein isoforms and the RBCC/TRIM motif. Oncogene 20, 7223–7233 (2001)

    CAS  Article  Google Scholar 

  38. Corada, M. et al. A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability. Blood 100, 905–911 (2002)

    CAS  Article  Google Scholar 

  39. Liao, F. et al. Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability. Cancer Res. 62, 2567–2575 (2002)

    CAS  PubMed  Google Scholar 

  40. Zhu, J., Lallemand-Breitenbach, V. & de The, H. Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission. Oncogene 20, 7257–7265 (2001)

    CAS  Article  Google Scholar 

  41. Lavau, C. et al. The acute promyelocytic leukaemia-associated PML gene is induced by interferon. Oncogene 11, 871–876 (1995)

    CAS  PubMed  Google Scholar 

  42. Chelbi-Alix, M. K. et al. Induction of the PML protein by interferons in normal and APL cells. Leukemia 9, 2027–2033 (1995)

    CAS  PubMed  Google Scholar 

  43. Sawyers, C. L. Will mTOR inhibitors make it as cancer drugs? Cancer Cell 4, 343–348 (2003)

    CAS  Article  Google Scholar 

  44. Vignot, S., Faivre, S., Aguirre, D. & Raymond, E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann. Oncol. 16, 525–537 (2005)

    CAS  Article  Google Scholar 

  45. Bernardi, R. et al. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nature Cell Biol. 6, 665–672 (2004)

    CAS  Article  Google Scholar 

  46. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004)

    CAS  Article  Google Scholar 

  47. Grisendi, S. et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 437, 147–153 (2005)

    ADS  CAS  Article  Google Scholar 

Download references

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.

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Correspondence to Pier Paolo Pandolfi.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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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