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The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence.
- Source :
-
Aging [Aging (Albany NY)] 2009 May 16; Vol. 1 (6), pp. 542-56. Date of Electronic Publication: 2009 May 16. - Publication Year :
- 2009
-
Abstract
- Oncogene-induced senescence acts as a barrier against tumour formation and has been implicated as the mechanism preventing the transformation of benign melanocytic lesions that frequently harbour oncogenic B-RAF or N-RAS mutations. In the present study we systematically assessed the relative importance of the tumour suppressor proteins p53, p21(Waf1), pRb and p16(INK4a) in mediating oncogene-induced senescence in human melanocytes. We now show that oncogenic N-RAS induced senescence in melanocytes is associated with DNA damage, a potent DNA damage response and the activation of both the p16(INK4a)/pRb and p53/p21(Waf1) tumour suppressor pathways. Surprisingly neither the pharmacological inhibition of the DNA damage response pathway nor silencing of p53 expression had any detectable impact on oncogene-induced senescence in human melanocytes. Our data indicate that the pRb pathway is the dominant effector of senescence in these cells, as its specific inactivation delays the onset of senescence and weakens oncogene-induced proliferative arrest. Furthermore, we show that although both p16(INK4a) and p21(Waf1) are upregulated in response to N-RAS(Q61K), the activities of these CDK inhibitors are clearly distinct and only the loss of p16(INK4a) weakens senescence. We propose that the ability of p16(INK4a) to inhibit the cyclin D-dependent kinases and DNA replication, functions not shared by p21(Waf1), contribute to its role in senescence. Thus, in melanocytes with oncogenic signalling only p16(INK4a) can fully engage the pRb pathway to alter chromatin structure and silence the genes that are required for proliferation.
- Subjects :
- Cell Line, Tumor
Cell Proliferation
Cellular Senescence genetics
Cyclin-Dependent Kinase Inhibitor p16 genetics
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Cyclin-Dependent Kinase Inhibitor p21 genetics
Cyclin-Dependent Kinase Inhibitor p21 metabolism
DNA Damage
Gene Silencing
Humans
Melanocytes cytology
Retinoblastoma genetics
Tumor Suppressor Protein p53 genetics
Melanocytes metabolism
Retinoblastoma metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1945-4589
- Volume :
- 1
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Aging
- Publication Type :
- Academic Journal
- Accession number :
- 20157537
- Full Text :
- https://doi.org/10.18632/aging.100051