Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
p53 plays a key role in DNA damage-induced apoptosis. Recent studies have reported that the phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis, although the underlying mechanisms have yet to be determined. Mdm2, a ubiquitin ligase for p53, plays a central...
Gespeichert in:
Veröffentlicht in: | The Journal of biological chemistry 2002-06, Vol.277 (24), p.21843-21850 |
---|---|
Hauptverfasser: | , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | p53 plays a key role in DNA damage-induced apoptosis. Recent studies have reported that the phosphatidylinositol 3-OH-kinase-Akt
pathway inhibits p53-mediated transcription and apoptosis, although the underlying mechanisms have yet to be determined. Mdm2,
a ubiquitin ligase for p53, plays a central role in regulation of the stability of p53 and serves as a good substrate for
Akt. In this study, we find that expression of Akt reduces the protein levels of p53, at least in part by enhancing the degradation
of p53. Both Akt expression and serum treatment induced phosphorylation of Mdm2 at Ser 186 . Akt-mediated phosphorylation of Mdm2 at Ser 186 had little effect on the subcellular localization of Mdm2. However, both Akt expression and serum treatment increased Mdm2
ubiquitination of p53. The serum-induced increase in p53 ubiquitination was blocked by LY294002, a phosphatidylinositol 3-OH-kinase
inhibitor. Moreover, when Ser 186 was replaced by Ala, Mdm2 became resistant to Akt enhancement of p53 ubiquitination and degradation. Collectively, these
results suggest that Akt enhances the ubiquitination-promoting function of Mdm2 by phosphorylation of Ser 186 , which results in reduction of p53 protein. This study may shed light on the mechanisms by which Akt promotes survival, proliferation,
and tumorigenesis. |
---|---|
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M109745200 |