Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase.
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.
Lin
Hui-Kuan
HK
George H.Whipple Laboratory for Cancer Research, Department of Pathology and The Cancer Center, University of Rochester, Rochester, NY 14642, USA.
Wang
Liang
L
Hu
Yueh-Chiang
YC
Altuwaijri
Saleh
S
Chang
Chawnshang
C
D000818:Animals; D002460:Cell Line / Q000378:metabolism; D002522:Chlorocebus aethiops; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D008025:Ligases / Q000737:chemistry / Q000502:physiology*; D046911:Macromolecular Substances; D051379:Mice; D009687:Nuclear Proteins; D010447:Peptide Hydrolases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D051381:Rats; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D008025:Ligases; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D010447:Peptide Hydrolases; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C497207:Mdm2 protein, mouse; C497208:Mdm2 protein, rat; C494920:Akt1 protein, rat; C061553:ATP dependent 26S protease