title: p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis.
abstract: The role of apoptosis in melanoma pathogenesis and chemoresistance is poorly characterized. Mutations in TP53 occur infrequently, yet the TP53 apoptotic pathway is often abrogated. This may result from alterations in TP53 family members, including the TP53 homologue TP63. Here we demonstrate that TP63 has an antiapoptotic role in melanoma and is responsible for mediating chemoresistance. Although p63 was not expressed in primary melanocytes, up-regulation of p63 mRNA and protein was observed in melanoma cell lines and clinical samples, providing the first evidence of significant p63 expression in this lineage. Upon genotoxic stress, endogenous p63 isoforms were stabilized in both nuclear and mitochondrial subcellular compartments. Our data provide evidence of a physiological interaction between p63 with p53 whereby translocation of p63 to the mitochondria occurred through a codependent process with p53, whereas accumulation of p53 in the nucleus was prevented by p63. Using RNA interference technology, both isoforms of p63 (TA and ΔNp63) were demonstrated to confer chemoresistance, revealing a novel oncogenic role for p63 in melanoma cells. Furthermore, expression of p63 in both primary and metastatic melanoma clinical samples significantly correlated with melanoma-specific deaths in these patients. Ultimately, these observations provide a possible explanation for abrogation of the p53-mediated apoptotic pathway in melanoma, implicating novel approaches aimed at sensitizing melanoma to therapeutic agents.
authors: Centre for Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England, UK.
authors: Rubeta N
authors: RN
authors: Matin
authors: Anissa
authors: A
authors: Chikh
authors: Stephanie Law Pak
authors: SL
authors: Chong
authors: David
authors: D
authors: Mesher
authors: Manuela
authors: M
authors: Graf
authors: Paolo
authors: P
authors: Sanza'
authors: Valentina
authors: V
authors: Senatore
authors: Maria
authors: M
authors: Scatolini
authors: Francesca
authors: F
authors: Moretti
authors: Irene M
authors: IM
authors: Leigh
authors: Charlotte M
authors: CM
authors: Proby
authors: Antonio
authors: A
authors: Costanzo
authors: Giovanna
authors: G
authors: Chiorino
authors: Rino
authors: R
authors: Cerio
authors: Catherine A
authors: CA
authors: Harwood
authors: Daniele
authors: D
authors: Bergamaschi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D011379:Prognosis; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C081876:CKAP4 protein, human; D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2