title: Senescence evasion in melanoma progression: uncoupling of DNA-damage signaling from p53 activation and p21 expression.
abstract: The best-established function of the melanoma-suppressor p16 is mediation of cell senescence, a permanent arrest following cell proliferation or certain stresses. The importance of p16 in melanoma suggests indolence of the other major senescence pathway through p53. Little or no p53 is expressed in senescent normal human melanocytes, but p16-deficient melanocytes can undergo p53-mediated senescence. As p16 expression occurs in nevi but falls with progression toward melanoma, we here investigated whether p53-dependent senescence occurs at some stage and, if not, what defects were detectable in this pathway, using immunohistochemistry. Phosphorylated checkpoint kinase 2 (CHEK2) can mediate DNA-damage signaling, and under some conditions senescence, by phosphorylating and activating p53. Remarkably, we detected no prevalent p53-mediated senescence in any of six classes of lesions. Two separate defects in p53 signaling appeared common: in nevi, lack of p53 phosphorylation by activated CHEK2, and in melanomas, defective p21 upregulation by p53 even when phosphorylated.
authors.affiliation: Biomedical Sciences Research Centre (Box J2A), St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Mackenzie Ross
authors.forename: Martin G
authors.initials: MG
authors.lastname: Cook
authors.forename: Heung
authors.initials: H
authors.lastname: Chong
authors.forename: Mehnaz
authors.initials: M
authors.lastname: Hossain
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pandha
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence; D064447:Checkpoint Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D018450:Disease Progression; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010858:Pigmentation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097796:Nucleolin
chemical_list: D064447:Checkpoint Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000097796:Nucleolin; C578634:CHEK2 protein, human