title: One, two, three--p53, p63, p73 and chemosensitivity.
abstract: Molecular links between apoptosis, tumorigenesis and drug resistance provide starting points for new therapeutic approaches and for a targeted cancer therapy. The discovery of the p53-related genes p63 and p73 raised the possibility that they may be cancer-associated genes and as a consequence that p53 is not the only component in predicting prognosis and response to chemotherapy, but instead the status of a network that contains p53, p73 and p63. This review focuses on the status and interrelationship of the p53 family members in human cancer as critical elements for tumor progression and response to therapy. Literature up to December 2006 is reviewed. p63 and p73--as well as p53--each use multiple promoters and alternative splicing to generate an array of isoforms, including full-length isoforms with a transactivation (TA-) domain homologous to that of full-length p53, and amino-terminally truncated (DeltaN-) isoforms. Whereas the full-length TA isoforms of p63 and p73 can activate downstream target genes and induce apoptosis, the DeltaN isoforms which lack the transactivation domain can act as dominant inhibitors of the full-length forms of p53, p63 and p73, inhibiting transactivation of target genes and induction of apoptosis. Deregulated dominant negative p63 and p73 isoforms play an oncogenic role in human cancer and contribute to chemoresistance. Thus, therapeutic modulation of TAp63/DeltaNp63, TAp73/DeltaNp73 and mutant p53 levels might be used to target the large percentage of human tumors that harbor p53 mutations and/or overexpress DeltaNp63 or DeltaNp73. Interfering with the expression or function of DeltaNp63 and/or DeltaNp73 and/or mutant p53 in tumor cells may render such tumors more responsive to therapy and reduce their aggressiveness and metastatic capacity.
authors.affiliation: Department of Internal Medicine IV, Hepatology and Gastroenterology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Martina_Mueller-Schilling@med.uni-heidelberg.de
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Elisa Schulze
authors.initials: ES
authors.lastname: Schleithoff
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Tobias
authors.initials: T
authors.lastname: Schilling
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human