A Role for p53 in Maintaining and Establishing the Quiescence Growth Arrest in Human Cells

The p53 tumor suppressor protein induces transient growth arrest or apoptosis in response to genotoxic stress and mediates the irreversible growth arrest of cellular senescence. We present evidence here that p53 also contributes to the reversible, growth factor-dependent arrest of quiescence (G0). M...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-05, Vol.277 (20), p.18206-18214
Main Authors: Itahana, Koji, Dimri, Goberdhan P., Hara, Eiji, Itahana, Yoko, Zou, Ying, Desprez, Pierre-Yves, Campisi, Judith
Format: Article
Language:English
Subjects:
ANIMAL CELLS
Antigens, Viral, Tumor - genetics
Antigens, Viral, Tumor - metabolism
BASIC BIOLOGICAL SCIENCES
Cell Cycle - physiology
Cells, Cultured
DNA Replication
Electrophoresis, Polyacrylamide Gel
Fibroblasts - cytology
GROWTH
GROWTH FACTORS
HUMAN POPULATIONS
Humans
INHIBITION
Microinjections
Resting Phase, Cell Cycle
RNA, Messenger - metabolism
Transcriptional Activation
Tumor Suppressor Protein p53 - physiology
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Summary:The p53 tumor suppressor protein induces transient growth arrest or apoptosis in response to genotoxic stress and mediates the irreversible growth arrest of cellular senescence. We present evidence here that p53 also contributes to the reversible, growth factor-dependent arrest of quiescence (G0). Microinjection of expression vectors encoding either MDM2 or a pRb-binding mutant of SV40 T antigen, both of which abrogate p53 function, stimulated quiescent normal human fibroblasts to initiate DNA synthesis and were 40–70% as effective as wild-type T antigen. Electrophoretic mobility shift and p53 transactivation assays showed that p53 activity was higher in quiescent and senescent cells compared with proliferating cells. As proliferating cells entered G0 after growth factor withdrawal, the p53 mRNA level increased, followed by transient accumulation of the protein. Shortly thereafter, the expression (mRNA and protein) of p21, a p53 target gene and effector of cell cycle arrest, increased. Finally, stable expression of the HPV16 E6 oncogene or dominant negative p53 peptide, GSE-22, both of which inhibit p53 function, delayed entry into quiescence following growth factor withdrawal. Our data indicate that p53 is activated during both quiescence and senescence. They further suggest that p53 activity contributes, albeit not exclusively, to the quiescent growth arrest.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M201028200