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c-myc and bcl-2 modulate p53 function by altering p53 subcellular trafficking during the cell cycle
J J Ryan1, E Prochownik, C A Gottlieb
1Department of Medicine, University of Michigan Medical Center, Ann Arbor 48109.
Summary
The oncogenes c-myc and bcl-2 cooperate to inhibit p53 tumor suppressor functions. Their coexpression prevents p53-induced apoptosis and cell cycle arrest by altering p53
Area of Science:
- Molecular Biology
- Cancer Research
- Oncogenes
Background:
- The p53 tumor suppressor protein plays a critical role in preventing cancer by inducing cell cycle arrest and apoptosis in response to cellular stress.
- Oncogenes such as c-myc and bcl-2 are frequently dysregulated in cancer and are known to promote cell proliferation and survival.
Purpose of the Study:
- To investigate the interplay between c-myc, bcl-2, and p53 in regulating cell fate.
- To determine how the expression of bcl-2 and c-myc influences p53-mediated cellular responses, including cell cycle arrest and apoptosis.
Main Methods:
- Coexpression of human Bcl-2 protein and p53 in murine erythroleukemia cells.
- Analysis of p53-mediated cell cycle arrest specificity.
- Investigation of the cooperative effects of c-myc and bcl-2 on p53 function.
- Assessment of subcellular trafficking of p53 in cotransfected cells.
Main Results:
- Coincident expression of Bcl-2 with p53 prolonged the survival of murine erythroleukemia cells.
- This effect was linked to a loss of G1 specificity in p53-mediated cell cycle arrest.
- Coexpression of bcl-2 and c-myc genes inhibited p53 functions, overcoming p53-induced apoptosis and cell cycle arrest.
- This inhibition was mediated by altered subcellular trafficking of p53, causing it to remain in the cytoplasm during a critical G1 phase period.
Conclusions:
- The oncogenes bcl-2 and c-myc cooperate to suppress p53 tumor suppressor activity.
- Altered p53 subcellular localization is a key mechanism by which bcl-2 and c-myc inhibit p53-dependent apoptosis and cell cycle arrest.
- These findings suggest a mechanism for the survival and proliferation of hematopoietic progenitors and highlight how aberrant bcl-2 and c-myc expression can contribute to cellular transformation.