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PMID: 12145204 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase.

The EMBO journal ·Vol. 21 ·No. 15 ·2002-08-01 ·Pages 4037-48

Lin HK, Wang L, Hu YC, Altuwaijri S, Chang C

Abstract

The androgen receptor (AR) controls several biological functions including prostate cell growth and apoptosis. However, the mechanism by which AR maintains its stability to function properly remains largely unknown. Here we show that Akt and Mdm2 form a complex with AR and promote phosphorylation-dependent AR ubiquitylation, resulting in AR degradation by the proteasome. The effect of Akt on AR ubiquitylation and degradation is markedly impaired in a Mdm2-null cell line compared with the wild-type cell line, suggesting that Mdm2 is involved in Akt-mediated AR ubiquitylation and degradation. Furthermore, we demonstrate that the E3 ligase activity of Mdm2 and phosphorylation of Mdm2 by Akt are essential for Mdm2 to affect AR ubiquitylation and degradation. These results suggest that phosphorylation-dependent AR ubiquitylation and degradation by Akt require the involvement of Mdm2 E3 ligase activity, a novel mechanism that provides insight into how AR is targeted for degradation.

MeSH Terms
Animals Cell Line/metabolism Chlorocebus aethiops Colony-Forming Units Assay Enzyme Activation Fibroblasts/metabolism Ligases/chemistry,physiology Macromolecular Substances Mice Nuclear Proteins Peptide Hydrolases/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Proteasome Endopeptidase Complex Protein Interaction Mapping Protein Processing, Post-Translational/physiology Protein Serine-Threonine Kinases Proto-Oncogene Proteins/chemistry,physiology Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-mdm2 Rats Receptors, Androgen/chemistry,metabolism Recombinant Fusion Proteins/physiology Transcription, Genetic Ubiquitin/metabolism Ubiquitin-Protein Ligases
Chemicals
Macromolecular Substances Nuclear Proteins Proto-Oncogene Proteins Receptors, Androgen Recombinant Fusion Proteins Ubiquitin Mdm2 protein, mouse Mdm2 protein, rat Proto-Oncogene Proteins c-mdm2 Ubiquitin-Protein Ligases Akt1 protein, rat Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Peptide Hydrolases Proteasome Endopeptidase Complex ATP dependent 26S protease Ligases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lin Hui-Kuan
George H.Whipple Laboratory for Cancer Research, Department of Pathology and The Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Wang Liang
Hu Yueh-Chiang
Altuwaijri Saleh
Chang Chawnshang
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf406
Published
2002-08-01
Pages
4037-48
Language
English
Region
England
NLM ID
8208664
PMCID
PMC126152
Subset
IM
Grants
NCI NIH HHS · CA51570 · United States
NCI NIH HHS · CA55639 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdf406 PMC Full Text View journal details
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