BRAFE600-associated senescence-like cell cycle arrest of human naevi (original) (raw)

Nature volume 436, pages 720–724 (2005)Cite this article

Abstract

Most normal mammalian cells have a finite lifespan1, thought to constitute a protective mechanism against unlimited proliferation2,3,4. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16INK4a (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes6; however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF7, a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma)8,9,10. This raises the question of whether naevi undergo BRAFV600E-induced senescence. Here we show that sustained BRAFV600E expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16INK4a and senescence-associated acidic β-galactosidase (SA-β-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-β-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16INK4a, suggesting that factors other than p16INK4a contribute to protection against BRAFV600E-driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAFV600E-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.

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Acknowledgements

We thank D. Atsma, E. Mesman and J. Zevenhoven for help with immunohistochemistry; S. Douma for analytical support; L. Oomen, L. Brocks and J. van Rheenen for help with microscopy; N. Gruis and C. Out for p16INK4a-deficient fibroblasts; L. Zaal and A. van der Wal for help with obtaining congenital naevus specimens; M. Voorhoeve and R. Agami for pRetroSuper, pRetroSuper-Blasticidin and pRetroSuper-GFP; S. Gryaznov for the telomere probe; R. Beijersbergen and M. van Lohuizen for reagents; G. Abou-Rjaily for help with lentiviral infections; P. Krimpenfort and colleagues in the Peeper laboratory for discussions; R. Bernards for support; and M. van Lohuizen and A. Berns for suggestions and reading of the manuscript. M.S.S is supported by an NIH grant. M.S.S. is a V Foundation for Cancer Research Scholar. L.C.W.V., T.K. and D.S.P. were supported by the Netherlands Organization for Scientific Research (NWO).

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Author notes

  1. Chrysiis Michaloglou, Liesbeth C. W. Vredeveld and Maria S. Soengas: *These authors contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Genetics,
    Chrysiis Michaloglou, Liesbeth C. W. Vredeveld, Thomas Kuilman & Daniel S. Peeper
  2. Division of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
    Donné M. Majoor
  3. Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500 E Medical Center Dr., Ann Arbor, Michigan, 48109, USA
    Maria S. Soengas & Christophe Denoyelle
  4. Department of Plastic, Reconstructive and Hand Surgery, Academic Medical Centre, PO Box 22660, G4-226, 1100 AZ, Amsterdam, The Netherlands
    Chantal M. A. M. van der Horst
  5. Department of Cell Biology and Harold Simmons Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Texas, 75390, Dallas, USA
    Jerry W. Shay
  6. Department of Pathology, Free University Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
    Wolter J. Mooi

Authors

  1. Chrysiis Michaloglou
  2. Liesbeth C. W. Vredeveld
  3. Maria S. Soengas
  4. Christophe Denoyelle
  5. Thomas Kuilman
  6. Chantal M. A. M. van der Horst
  7. Donné M. Majoor
  8. Jerry W. Shay
  9. Wolter J. Mooi
  10. Daniel S. Peeper

Corresponding authors

Correspondence toWolter J. Mooi or Daniel S. Peeper.

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

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Michaloglou, C., Vredeveld, L., Soengas, M. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi.Nature 436, 720–724 (2005). https://doi.org/10.1038/nature03890

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Editorial Summary

Cell senescence and cancer

Cellular senescence, a growth-arrest program that limits the lifespan of mammalian cells and prevents unlimited cell proliferation, is attracting considerable interest because of its links to tumour suppression. Using a mouse model in which the oncogene Ras is activated in the haematopoietic compartment of bone marrow, Braig et al. show that cellular senescence can block lymphoma development. Genetic inactivation of the histone methyltransferase Suv39h1 that controls senescence by ‘epigenetic’ modification of DNA-associated proteins, or a pharmacological approach that mimics loss of this enzyme, allow the formation of malignant lymphomas in response to oncogenic Ras. This work has important implications for both tumour development and tumour therapy. Michaloglou et al. report that oncogene-induced senescence may be a physiologically important process in humans, keeping moles in a benign state for many years: unchecked they develop into malignant melanomas. Chen et al. also find that cellular senescence blocks tumorigenesis in vivo: they show that acting together, the p53 tumour suppressor and the cellular senescence system can prevent prostate cancer induction in mice by the PTEN mutation. Collado et al. show that cellular senescence is a defining feature of Ras-initiated premalignant tumours; this could prove valuable in the diagnosis and prognosis of cancer.

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