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p53 Activation by nitric oxide involves down-regulation of Mdm2
Xinjiang Wang1, Dan Michael, Gilbert de Murcia
1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
The Journal of Biological Chemistry
|February 28, 2002
Summary
Nitric oxide (NO) activates the p53 tumor suppressor protein by reducing Mdm2 levels, leading to p53 accumulation. This NO-mediated p53 activation occurs independently of ATM, PARP1, or ARF.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Biochemistry
Background:
- Nitric oxide (NO) is a key signaling molecule in physiological and pathological processes.
- NO can induce cellular stress by damaging proteins and DNA.
- Previous studies suggest NO activates the p53 tumor suppressor protein, but mechanisms are unclear.
Purpose of the Study:
- To elucidate the mechanisms by which NO activates the p53 tumor suppressor protein.
- To investigate the role of Mdm2 in NO-induced p53 activation.
Main Methods:
- Utilized various cell types, including mouse embryonic fibroblasts.
- Assessed p53 and Mdm2 protein levels and p53 ubiquitination.
- Investigated the requirement for ATM, poly(ADP-ribose) polymerase 1 (PARP1), and ARF in NO signaling to p53.
Main Results:
- NO induces the accumulation of transcriptionally active p53 across multiple cell types.
- NO signaling to p53 does not require ATM, PARP1, or ARF.
- NO causes a p53-independent decrease in Mdm2 protein levels, preceding p53 accumulation.
- Reduced Mdm2 levels correlate with decreased p53 ubiquitination.
Conclusions:
- NO activates p53 by down-regulating Mdm2 protein levels.
- This mechanism of p53 activation by NO is independent of canonical stress response pathways involving ATM, PARP1, and ARF.