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p21WAF1/CIP1/SDI1 is elevated through a p53-independent pathway by mimosine
1Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Abstract:
Tumor suppressor p53 is a nuclear protein that is induced by DNA damage and is involved in G1 and G2 phase control of the cell cycle. p21WAF1/CIP1/SDI1 (p21), a cyclin-dependent kinase inhibitor, is a downstream target and effector of p53 to induce G1 arrest. Mimosine is a potent reversible late G1 phase blocker of the cell cycle. In this study, we showed that mimosine can increase both p21 mRNA and protein levels, indirectly inhibit cyclin E-associated kinase activity without affecting the cyclin E protein level, block human breast cancer cells (21PT) in the late G1 phase of the cell cycle, and induce a p53-independent p21 pathway in these cells. These results support the possibility of restoring a G1 checkpoint by use of mimosine. They also suggest that the mechanism of the effect of mimosine is complex and may have more than one target in the cell.
Insights
Mimosine, a cell cycle blocker, increases p21 levels and inhibits cyclin E activity, inducing a G1 phase arrest in breast cancer cells. This suggests mimosine can restore the G1 checkpoint via a p53-independent pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The p53 tumor suppressor regulates cell cycle control, particularly the G1 and G2 phases.
- p21WAF1/CIP1/SDI1 (p21) is a key downstream effector of p53, inducing G1 arrest.
- Mimosine is a known reversible inhibitor of late G1 phase progression.
Purpose of the Study:
- To investigate the effects of mimosine on the cell cycle and p21 pathway in human breast cancer cells.
- To determine if mimosine can restore a functional G1 checkpoint.
Main Methods:
- Treatment of 21PT human breast cancer cells with mimosine.
- Analysis of p21 mRNA and protein expression.
- Assessment of cyclin E-associated kinase activity.
- Cell cycle phase analysis.
Main Results:
- Mimosine increased both p21 mRNA and protein levels.
- Cyclin E-associated kinase activity was indirectly inhibited by mimosine.
- Human breast cancer cells were blocked in the late G1 phase.
- Mimosine induced a p53-independent p21 pathway.
Conclusions:
- Mimosine can restore a G1 checkpoint in human breast cancer cells.
- The mechanism of mimosine involves a p53-independent induction of p21.
- Mimosine's complex mechanism may involve multiple cellular targets.