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 func...

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Bibliographic Details
Published in:Cancer cell 2003-04, Vol.3 (4), p.403-410
Main Authors: Irwin, Meredith S, Kondo, Keiichi, Marin, Maria Carmen, Cheng, Lynn S, Hahn, William C, Kaelin, William G
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis - genetics
Blotting, Western
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - drug effects
DNA-Binding Proteins - physiology
Drug Resistance, Neoplasm - genetics
Embryo, Mammalian
Fibroblasts - physiology
Genes, p53 - drug effects
Genes, Tumor Suppressor
Humans
In Situ Nick-End Labeling
Mice
Mutation
Nuclear Proteins - antagonists & inhibitors
Nuclear Proteins - drug effects
Nuclear Proteins - physiology
RNA, Small Interfering - metabolism
Tumor Cells, Cultured
Tumor Protein p73
Tumor Suppressor Proteins
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/S1535-6108(03)00078-3