Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53*
By Y. Ogawara, Shohei Kishishita, T. Obata, Yuko Isazawa, Toshiaki Suzuki, Keiji Tanaka, Norihisa Masuyama, Y. Gotoh. Journal of Biological Chemistry, 2002
645 citations recorded by the source corpus.
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 Ser186. Akt-mediated phosphorylation of Mdm2 at Ser186 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 Ser186 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 Ser186, which results in reduction of p53 protein. This study may shed light on the mechanisms by which Akt promotes survival, proliferation, and tumorigenesis.
Subfields: Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/bca1d1791eb8e2056d050c2ab2b91129d0d06de7
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Citations in the corpus
- Ribosomal Protein L11 Negatively Regulates Oncoprotein MDM2 and Mediates a p53-Dependent Ribosomal-Stress Checkpoint Pathway (2003, background): “The 491 residues of HDM2 can be divided into three functional domains: an N-terminal region which binds p53, a Cterminal RING finger domain that promotes p53 ubiquitination, and a central region of approximately 300 residues that contains multiple sites for binding and regulation by different protei”
- p53 represses c-Myc through induction of the tumor suppressor miR-145 (2009, background): “degradation, inactivation (dephosphorylation) of Akt increases the stability of p53 (16).”
- PI3K/Akt: getting it right matters (2008, background): “Two proposed mechanisms of Aktdependent regulation of Mdm2 include the Akt-dependent increase of Mdm2’s nuclear import (Mayo and Donner, 2001) and its intrinsic ubiquitin ligase activity (Zhou et al., 2001; Ashcroft et al., 2002; Ogawara et al., 2002).”
- Hydrogen peroxide sensing, signaling and regulation of transcription factors (2014, background): “On the other hand the phosphorylation of MDM2 through the PI3K/AKT pathway promotes MDM2 nuclear import, resulting in TP53 nuclear export [278][279][280].”
- PI3K/Akt and apoptosis: size matters (2003, background): “Two alternative mechanisms of Aktdependent regulation of Mdm2/HDM2 have been described, and they include the induction of Mdm2 nuclear import (Mayo and Donner, 2001) or the regulation of Mdm2/HDM2-ubiquitin ligase enzymatic activity (Zhou et al., 2001b; Ashcroft et al., 2002; Ogawara et al., 2002).”
- Signal transduction in cancer. (2015, background): “Last, Akt-induced ubiquitylation anddegradation of p53 suppresses p53-induced apoptosis (Ogawara et al. 2002).”
- Growing roles for the mTOR pathway. (2005, background): “Akt/PKB is a key component of the insulin/PI3K signaling pathway and modulates cell survival and proliferation through downstream substrates such as the FOXO class of transcription factors (reviewed in [42]) and the p53-regulator mdm2 [43,44].”