Abstract
Contrary to malignant melanoma, nevi are a benign form of melanocytic hyperproliferation. They are frequently observed as precursor lesions of melanoma, but they also feature biochemical markers of senescence. In particular, evidence for oncogene-induced melanocyte senescence as natural means to prevent tumorigenesis has been obtained in nevi with mutated B-RafV600E. Here, we demonstrate that strong oncogenic growth factor receptor signalling drives melanocytes into senescence, whereas weaker signals keep them in the proliferative state. Activation of oncogene-induced senescence also produces multinucleated giant cells, a long known histological feature of nevus cells. The protein levels of the senescence mediators, p53 and pRB, and their upstream activators do not correlate with senescence. However, strong oncogene signalling leads to pronounced reactive oxygen stress, and scavenging of reactive oxygen species (ROS) efficiently prevents the formation of multinucleated cells and senescence. Similarly, expression of oncogenic N-RAS results in ROS generation, DNA damage and the same multinuclear senescent phenotype. Hence, we identified oncogenic signalling-dependent ROS production as critical mediator of the melanocytic multinuclear phenotype and senescence, both of them being hallmarks of human nevus cells.
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Abbreviations
- ATM:
-
ataxia telangiectasia mutated
- ARF:
-
alternative reading frame
- CDKN2A:
-
cyclin-dependent kinase inhibitor 2A
- Chk2:
-
checkpoint kinase 2
- CKI:
-
cyclin-dependent kinase inhibitor
- DCF:
-
2′,7′-dichlorofluorescein
- EGF:
-
epidermal growth factor
- EGFR:
-
epidermal growth factor receptor
- Hm:
-
HERmrk
- INK4A:
-
inhibitor of cyclin-dependent kinase 4A
- INK4B:
-
inhibitor of cyclin-dependent kinase 4B
- NAC:
-
N-acetylcysteine
- ROS:
-
reactive oxygen species
- RTK:
-
receptor tyrosine kinase
- SA-β-gal:
-
senescence-associated β-galactosidase
- Xmrk:
-
Xiphophorus melanoma receptor kinase
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Acknowledgements
We thank Dr Thorsten Stiewe for kindly providing the PAB 122 hybridoma supernatant and Professor Jürgen Hoppe for his help with the time lapse experiment. In addition, we thank Johannes Haydn for generating the melan a pWHE459 cell lines and Toni Wagner for great technical support. This work was supported by the Deutsche Forschungsgesellschaft, Transregio 17 (‘RAS-dependent pathways in human cancer’). CL was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Wurzburg.
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Leikam, C., Hufnagel, A., Schartl, M. et al. Oncogene activation in melanocytes links reactive oxygen to multinucleated phenotype and senescence. Oncogene 27, 7070–7082 (2008). https://doi.org/10.1038/onc.2008.323
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DOI: https://doi.org/10.1038/onc.2008.323
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