Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases.

Abstract

Androgen receptor (AR) plays a pivotal role in prostate cancer. Regulation of AR transcriptional activity by post-translational modifications, such as phosphorylation by multiple kinases, is well documented. Here, we report that two PIM-1 kinase isoforms which are up-regulated during prostate cancer progression, namely PIM-1S and PIM-1L, modulate AR stability and transcriptional activity through differentially phosphorylating AR at serine 213 (Ser-213) and threonine 850 (Thr-850). Although both kinases are capable of interacting with and phosphorylating AR at Ser-213, only PIM-1L could phosphorylate Thr-850. We also showed that PIM-1S induced Ser-213 phosphorylation destabilizes AR by recruiting the ubiquitin E3 ligase Mdm2 and promotes AR degradation in a cell cycle-dependent manner, while PIM-1L-induced Thr-850 phosphorylation stabilizes AR by recruiting the ubiquitin E3 ligase RNF6 and promotes AR-mediated transcription under low-androgen conditions. Furthermore, both PIM-1 isoforms could promote prostate cancer cell growth under low-androgen conditions. Our data suggest that these kinases regulate AR stability and transcriptional activity through recruitment of different functional partners in a phosphorylation-dependent manner. As AR turnover has been previously shown to be critical for cell cycle progression in prostate cancer cells, PIM-1 kinase isoforms may promote prostate cancer cell growth, at least in part, through modulating AR activity via distinct mechanisms.

• Authors: Douglas E Linn, Xi Yang, Yingqiu Xie, Alan Alfano, Dhanraj Deshmukh, Xin Wang, Hermela Shimelis, Hegang Chen, Wei Li, Kexin Xu, Mingyuan Chen, Yun Qiu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 27 Pg. 22959-68 (Jun 29 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22584579 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• RNF6 protein, human
• Receptors, Androgen
• Ubiquitin-Protein Ligases
• PIM1 protein, human
• Proto-Oncogene Proteins c-pim-1

Topics

• Animals
• COS Cells
• Cell Cycle (physiology)
• Chlorocebus aethiops
• DNA-Binding Proteins (metabolism)
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Humans
• Male
• Phosphorylation (physiology)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Proto-Oncogene Proteins c-pim-1 (genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)
• Transcription, Genetic (physiology)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination (physiology)