1. Division of Molecular Genetics and
2. Division of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
3. Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500 E Medical Center Dr. Ann Arbor, Michigan 48109, USA
4. Department of Plastic, Reconstructive and Hand Surgery, Academic Medical Centre, PO Box 22660 G4-226, 1100 AZ Amsterdam, The Netherlands
5. Department of Cell Biology and Harold Simmons Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
6. Department of Pathology, Free University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
7. *These authors contributed equally to this work

Correspondence to: Wolter J. Mooi⁶Daniel S. Peeper¹ Correspondence and requests for materials should be addressed to D.S.P. (Email: d.peeper@nki.nl) or W.J.M. (Email: wj.mooi@vumc.nl).

Abstract

Most normal mammalian cells have a finite lifespan¹, thought to constitute a protective mechanism against unlimited proliferation^{2, 3, 4}. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16^INK4a (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 BRAF^V600E-induced senescence. Here we show that sustained BRAF^V600E expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16^INK4a and senescence-associated acidic -galactosidase (SA--Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA--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 p16^INK4a, suggesting that factors other than p16^INK4a contribute to protection against BRAF^V600E-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, BRAF^V600E-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.

1. Division of Molecular Genetics and
2. Division of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
3. Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500 E Medical Center Dr. Ann Arbor, Michigan 48109, USA
4. Department of Plastic, Reconstructive and Hand Surgery, Academic Medical Centre, PO Box 22660 G4-226, 1100 AZ Amsterdam, The Netherlands
5. Department of Cell Biology and Harold Simmons Cancer Center, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
6. Department of Pathology, Free University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
7. *These authors contributed equally to this work

Correspondence to: Wolter J. Mooi⁶Daniel S. Peeper¹ Correspondence and requests for materials should be addressed to D.S.P. (Email: d.peeper@nki.nl) or W.J.M. (Email: wj.mooi@vumc.nl).

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