Interactions Between p53 and MDM2 in a Mammalian Cell Cycle Checkpoint Pathway

Normal p53 function is required for optimal arrest of cells in the G1phase of the cell cycle following certain types of DNA damage. Loss of this cell cycle checkpoint may contribute to tumor development by increasing the number of genetic abnormalities in daughter cells following DNA damage. The MDM...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-03, Vol.91 (7), p.2684-2688
Main Authors: Chen, Chaw-Yuan, Oliner, Jonathan D., Zhan, Qimin, Fornace, Albert J., Vogelstein, Bert, Kastan, Michael B.
Format: Article
Language:English
Subjects:
Animals
Cell cycle
Cell Cycle - physiology
Cell lines
Cells
Cellular biology
Daughter cells
Deoxyribonucleic acid
DNA
DNA Damage
G1 Phase - physiology
Gamma Rays
Gene Expression Regulation, Neoplastic
Genes
Irradiation
Mammalia
Mammals
Messenger RNA
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Nuclear Proteins
p53 genes
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-mdm2
Transcription, Genetic - radiation effects
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - metabolism
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Summary:Normal p53 function is required for optimal arrest of cells in the G1phase of the cell cycle following certain types of DNA damage. Loss of this cell cycle checkpoint may contribute to tumor development by increasing the number of genetic abnormalities in daughter cells following DNA damage. The MDM2 protein is an endogenous gene product that binds to the p53 protein and is able to block p53-mediated transactivation of cotransfected reporter constructs; thus, interactions between MDM2 and p53 in this checkpoint pathway following ionizing irradiation were examined. Though increases in p53 protein by DNA damage were not abrogated by MDM2 over-expression, increased levels of MDM2, resulting either from endogenous gene amplification or from transfection of an exogenous expression vector, were associated with a reduction in the ability of cells to arrest in G1following irradiation. In addition, expression of endogenous MDM2 was enhanced by ionizing irradiation at the level of transcription in a p53-dependent fashion. These observations demonstrate that MDM2 overexpression can inhibit p53 function in a known physiologic pathway and are consistent with the hypothesis that MDM2 may function in a "feedback loop" mechanism with p53, possibly acting to limit the length or severity of the p53-mediated arrest following DNA damage
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.7.2684