TY - JOUR
T1 - BRAFE600-associated senescence-like cell cycle arrest of human naevi
AU - Michaloglou, Chrysiis
AU - Vredeveld, Liesbeth C W
AU - Soengas, Maria S.
AU - Denoyelle, Christophe
AU - Kuilman, Thomas
AU - Van Der Horst, Chantal M A M
AU - Majoor, Donné M.
AU - Shay, Jerry W.
AU - Mooi, Wolter J.
AU - Peeper, Daniel S.
N1 - Funding Information:
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).
PY - 2005/8/4
Y1 - 2005/8/4
N2 - Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. 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 oncogenes; 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 BRAF, 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). 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.
AB - Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. 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 oncogenes; 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 BRAF, 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). 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.
UR - http://www.scopus.com/inward/record.url?scp=23244447037&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23244447037&partnerID=8YFLogxK
U2 - 10.1038/nature03890
DO - 10.1038/nature03890
M3 - Article
C2 - 16079850
AN - SCOPUS:23244447037
SN - 0028-0836
VL - 436
SP - 720
EP - 724
JO - Nature
JF - Nature
IS - 7051
ER -