title: BTG2 is an LXXLL-dependent co-repressor for androgen receptor transcriptional activity.
abstract: The tumor suppressor gene, BTG2 has been down-regulated in prostate cancer and the ectopic expression of this gene has been shown to inhibit prostate cancer cell growth. Sequence analysis revealed that the BTG2 protein contains two leucine-rich motifs ((20)LxxLL(24) and (92)LxxLL(96)), which are usually found in nuclear receptor co-factors. Based on this, we postulated that there will be an association between BTG2 and AR. In this study, we discovered that BTG2 directly bound to the androgen receptor (AR) in the absence of 5α-dihydrotestosterone (DHT), and in the presence of the androgen, this interaction was increased. BTG2 bearing the mutant (20)LxxLL(24) motif bound to AR equally efficient as the wild-type BTG2, while BTG2 bearing the mutant (92)LxxLL(96) motif failed to interact with AR. Functional studies indicated that ectopic expression of BTG2 caused a significant inhibition of AR-mediated transcriptional activity and a decreased growth of prostate cancer cells. Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2. The intact (92)LxxLL(96) motif is required for these activities. These findings, for the first time, demonstrate that BTG2 complexes with AR via an LxxLL-dependent mechanism and may play a role in prostate cancer via modulating the AR signaling pathway.
authors.affiliation: School of Radiation Medicine and Public Health, Medical College of Soochow University, Suzhou 215123, China.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Hu
authors.forename: Qing-Hui
authors.initials: QH
authors.lastname: Meng
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.forename: Chun-Min
authors.initials: CM
authors.lastname: Ge
authors.forename: Asha
authors.initials: A
authors.lastname: Jacob
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Eliot M
authors.initials: EM
authors.lastname: Rosen
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
mesh_terms: D043582:5-alpha-Dihydroprogesterone / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D016350:Leucine Zippers; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D017874:Immediate-Early Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D043582:5-alpha-Dihydroprogesterone