Journal
DRUG RESISTANCE UPDATES
Volume 9, Issue 6, Pages 288-306Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.drup.2007.01.001
Keywords
apoptosis; chemosensitivity; p53; p63; p73; drug resistance
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Funding
- Medical Research Council [MC_U132670600] Funding Source: Medline
- Medical Research Council [MC_U132670600] Funding Source: researchfish
- MRC [MC_U132670600] Funding Source: UKRI
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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 (AN-) isoforms. Whereas the full-length TA isoforms of p63 and p73 can activate downstream target genes and induce apoptosis, the Delta N 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/Delta Np63, TAp73/Delta Np73 and mutant p53 levels might be used to target the large percentage of human tumors that harbor p53 mutations and/or overexpress Delta Np63 or Delta Np73. Interfering with the expression or function of Delta Np63 and/or Delta Np73 and/or mutant p53 in tumor cells may render such tumors more responsive to therapy and reduce their aggressiveness and metastatic capacity. (c) 2007 Elsevier Ltd. All rights reserved.
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