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Tumor-promoting phorbol ester transiently down-modulates the p53 level and blocks the cell cycle
J Skouv1, P O Jensen, J Forchhammer
1Department of Molecular Oncology, Danish Cancer Society, Copenhagen.
Cell Growth & Differentiation : the Molecular Biology Journal of the American Association for Cancer Research
|March 1, 1994
Summary
Tumor promoters like PMA decrease p53 mRNA and protein levels by activating protein kinase C. This leads to a transient G1 cell cycle block, suggesting p53 phosphorylation is key to regulating expression and cell cycle progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Protein kinase C (PKC) signaling is activated by tumor promoters.
- p53 is a critical tumor suppressor protein.
- Regulation of p53 expression impacts cell cycle control.
Purpose of the Study:
- To investigate the effect of PKC activation on p53 mRNA and protein levels.
- To determine the mechanism of p53 down-regulation by tumor promoters.
- To analyze the impact of p53 modulation on cell cycle progression.
Main Methods:
- Treatment of human cell lines (HeLa, A549) with phorbol ester (PMA) and okadaic acid.
- Measurement of p53 mRNA and protein levels.
- Analysis of transcriptional rates and mRNA stability.
- Inhibition of protein synthesis with cycloheximide.
- Flow cytometric cell cycle analysis.
Main Results:
- PMA and okadaic acid decreased p53 mRNA levels in various cell lines.
- PMA induced a transient decrease in p53 mRNA and protein in HeLa and A549 cells.
- The decrease in p53 mRNA was not due to altered transcription or stability.
- Cycloheximide abolished PMA-induced p53 mRNA down-regulation.
- PMA treatment caused a transient G1 cell cycle block.
Conclusions:
- PKC activation by tumor promoters down-regulates p53 expression.
- A short-lived protein mediates the PMA-induced decrease in p53 mRNA.
- p53 phosphorylation by PKC may be crucial for p53 expression regulation.
- PKC-induced p53 modulation contributes to cell cycle arrest.