title: 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.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Linn
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Xie
authors.forename: Alan
authors.initials: A
authors.lastname: Alfano
authors.forename: Dhanraj
authors.initials: D
authors.lastname: Deshmukh
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Hermela
authors.initials: H
authors.lastname: Shimelis
authors.forename: Hegang
authors.initials: H
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Kexin
authors.initials: K
authors.lastname: Xu
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Qiu
mesh_terms: D000818:Animals; D019556:COS Cells; D002453:Cell Cycle / Q000502:physiology; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010766:Phosphorylation / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C119753:RNF6 protein, human; D011944:Receptors, Androgen; D044767:Ubiquitin-Protein Ligases; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1