Chemosensitivity linked to p73 function.
Most chemotherapeutic agents induce DNA damage, leading to p53 accumulation and apoptosis. The factors that determine chemosensitivity in p53-defective tumor cells are poorly understood. We found that the p53 family member p73 is induced by a wide variety of chemotherapeutic drugs. Blocking p73 function with a dominant-negative mutant, siRNA, or homologous recombination led to chemoresistance of human tumor cells and engineered transformed cells, irrespective of p53 status. Mutant p53 can inactivate p73 and downregulation of mutant p53 enhanced chemosensitivity. These findings indicate that p73 is a determinant of chemotherapeutic efficacy in humans.
Dana-Farber Cancer Institute and Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02115, USA.
Meredith S
MS
Irwin
Keiichi
K
Kondo
Maria Carmen
MC
Marin
Lynn S
LS
Cheng
William C
WC
Hahn
William G
WG
Kaelin
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000502:physiology; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins