Liganded Androgen Receptor Interaction with β-Catenin

Pawlowski, John E.; Ertel, Jessica; Allen, Mary A.; Xu, Mei; Butler, Cheryl; Wilson, Elizabeth M.; Wierman, Margaret E.

doi:10.1074/jbc.m200545200

Cited by 157 publications

(66 citation statements)

References 58 publications

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“…It is not surprising that ␤-catenin and SF1 synergistically activate the MISRII promoter. ␤-Catenin interacts with a number of factors to exert its biological effects, the nuclear hormone receptor RXR and androgen receptors among them (25,26).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Cooperation between the β-Catenin Signaling Pathway and Steroidogenic Factor 1 in the Activation of the Mullerian Inhibiting Substance Type II Receptor

Hossain

Saunders

2003

Journal of Biological Chemistry

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Mullerian inhibiting substance type II receptor (MISRII) is a member of the transforming growth factor-␤ superfamily. Mutations in mullerian inhibiting substance (MIS) or MISRII cause male sexual abnormalities, persistent mullerian duct syndrome, and pseudohermaphroditism. The spatial and temporal regulation of MIS and MISRII is important for its biological action. Male Wnt7a mutant mice do not undergo regression of mullerian ducts. Here we showed that the canonical Wnt signaling pathway regulated MISRII. The promoter MISRII was activated by ␤-catenin expression, and this activation was dependent on TCF4-binding sites. The nuclear receptor superfamily member steroidogenic factor 1 (SF1) synergistically activated the MISRII promoter with ␤-catenin. APC, a negative regulator of Wnt signaling, decreased SF1-mediated activation of the MISRII promoter in the colon carcinoma cell line SW480. We also showed a direct physical interaction between ␤-catenin and SF1 by co-immunoprecipitation. Thus, our findings suggest that MISRII is a developmental target of Wnt7a signaling for mullerian duct regression during sexual differentiation.

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Section: Discussionmentioning

confidence: 99%

Synergistic Cooperation between the β-Catenin Signaling Pathway and Steroidogenic Factor 1 in the Activation of the Mullerian Inhibiting Substance Type II Receptor

Hossain

Saunders

2003

Journal of Biological Chemistry

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“…For example, PTEN regulates, by way of altered GSK3b function, the localization of b-catenin, its transcriptional effector, T-cell factor (Tcf) (Persad et al, 2001b;Sharma et al, 2002) and its target cell cycle regulator, cyclin D1 (Radu et al, 2003). Loss of PTEN may, therefore, result in increased nuclear localization of AR/b-catenin complexes (Mulholland et al, 2002;Pawlowski et al, 2002), potentially leading to alteration of cell cycle events or ligand specificity of AR. A logical extrapolation is that PTEN loss may promote AR gain-of-function by modulating other known AR coregulators including ARA70 (Yeh and Chang, 1996) and ARA54 (Kang et al, 1999), thereby permitting responsiveness to low androgen levels or nonandrogen ligands.…”

Section: Loss Of Pten Provides a Gain-of-function 'Environment' For Armentioning

confidence: 99%

“…b-Catenin can enhance cell proliferation (Mulholland et al, 2003;Masiello et al, 2004), production of PSA and increase AR responsiveness to nonandrogen ligands, including estrogens (Truica et al, 2000;Pawlowski et al, 2002;Song et al, 2003b;Mulholland et al, 2003;. Mice with prostate-specific deletion of the b-catenin regulatory domain (Dexon 3) are reported to develop metaplasia and, in some instances, neoplastic transformation (Bierie et al, 2003;Gounari et al, 2002).…”

Section: Pi3k/akt and Ar: Critical Regulators Of Progression To Ai Prcamentioning

confidence: 99%

PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

Mulholland

Dedhar

Wu³

et al. 2006

Oncogene

201

164

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Prostate cancer (PrCa) is characterized by progression from an androgen-dependent phenotype to one that is inevitably androgen independent (AI) and lethal. Recent evidence strongly suggests that the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and androgen receptor (AR) signalling pathways provide prostatic epithelium with the necessary signalling events to escape the apoptotic response associated with androgen withdrawal therapy. Silencing of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and glycogen synthase kinase b (GSK3b) are frequently associated with advanced PrCa systems and likely serve critical roles in promoting AR and PI3K/Akt gain-of-function. That PTEN negatively regulates AR and is sufficient to promote metastatic PrCa in murine models strongly implies its role as a gatekeeper of progressive PrCa. In human PrCa, PTEN loss is correlated with substantial increases in Akt Ser473 and integrin-linked kinase expression, both of which promote Ser 9 phospho-inhibition of GSK3b and inactivation of apoptotic factors. Sufficient evidence also suggests that GSK3b is not only a critical regulator of proproliferative signalling but also a promiscuous one as PI3K/Akt pools of GSK3b are, at least in part, functionally interchangeable with those of the Wnt/b-catenin pathway. Thus, GSK3b may serve not only as a mediator of PI3K/Akt activation but may also regulate the potent transactivation and proproliferative effects that Wnt3a and b-catenin confer upon AR. These data suggest that prostate-specific activation of GSK3b may serve as a viable pharmacological option. Thus, in this review, we emphasize that temporal changes in GSK3b and PTEN expression during progression to AI PrCa are important factors when considering the potential for therapies targeting the oncogenic contributions of PI3K/Akt and AR signalling pathways.

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“…b-Catenin has also been described as a liganddependent coactivator of the AR (Truica et al, 2000;Mulholland et al, 2002;Pawlowski et al, 2002;Yang et al, 2002). Previously, we have shown that translocating AR can provide a means of nuclear entry and accumulation of b-catenin (Mulholland et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we have shown that translocating AR can provide a means of nuclear entry and accumulation of b-catenin (Mulholland et al, 2002). This mode of b-catenin trafficking has also been shown to hold true in neuronal cells (Pawlowski et al, 2002). Cotrafficking of AR and b-catenin to the nucleus likely has important implications both for AR and Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Functional localization and competition between the androgen receptor and T-cell factor for nuclear β-catenin: a means for inhibition of the Tcf signaling axis

Mulholland¹,

Read²,

Rennie³

et al. 2003

Oncogene

107

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Recent reports suggest that the b-catenin-T-cell factor (Tcf ) (BCT) signaling pathway is important in the progression of prostate cancer. Evidence suggests that the androgen receptor (AR) can repress BCT-mediated transcription both in prostate cancer and colon cancer cells . In this study, we validate such findings and show that repression of BCT signaling is facilitated by competition between the AR and Tcf. Measurements of the Tcf transcriptional reporter (TOP-FLASH) indicated that AR þ DHT-mediated repression can inhibit BCT transcription in the presence of WT and exogenous activating b-catenin (D1-130 bp). Transient transfections in SW480 cells (APC mut/mut ) showed that this mode of repression is functionally independent of APCmediated b-catenin ubiquitination. Using a recently developed red flourescent protein (HcRed), we demonstrate novel observations about the nuclear distribution of Tcf. Furthermore, with the use of red (HcRed-AR and HcRed-Tcf) and green fusion proteins (b-catenin-EGFP), we provide morphological evidence of a reciprocal balance of nuclear b-catenin-EGFP (BC-EGFP). By cotransfecting in LNCaP prostate tumor cells and using quantitative imaging software, we demonstrated a 62.0% colocalization of HcRed-AR and BC-EGFP in the presence of DHT and 63.3% colocalization of HcRed-Tcf/BC-EGFP in the absence of DHT. Costaining for activated RNA Pol II (phosphoserine 2) and HcRed-Tcf suggested that Tcf foci contain transcriptional 'hotspots' validating that these sites have the capacity for transcriptional activity. Given this apparent androgen-dependent competition for nuclear BC-EGFP, we chose to assess our hypothesis by in vivo and in vitro binding assays. SW480 cells transiently transfected with an AR expression construct, treated with DHT and immunoprecipitated for Tcf showed less associated b-catenin when compared to Tcf precipitates from untreated cells. Furthermore, by treating cells with DHT þ Casodex, we were able to abrogate the androgensensitive AR/b-catenin interaction, in addition to relieving transcriptional repression of the TOPFLASH reporter. In vitro binding assays, with increasing amounts of AR S35 , resulted in decreased Tcf S35 association with immunoprecipitated recombinant b-catenin-HIS. These data suggest that in steady-state conditions, AR has the ability to compete out Tcf binding for b-catenin. Finally, using SW480 cells, we show that AR-mediated repression of the BCT pathway has implications for cell cycle progression and in vitro growth. Using FACs analysis, we observed a 26.1% increase in accumulation of cells in the G1 phase of the cell cycle, while in vitro growth assays showed a 35% reduction in viable cells transfected with AR þ DHT treatment. Together, our data strongly suggest that a reciprocal balance of nuclear b-catenin facilitates ARmediated repression of BCT-driven transcription and cell growth.

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Liganded Androgen Receptor Interaction with β-Catenin

Cited by 157 publications

References 58 publications

Synergistic Cooperation between the β-Catenin Signaling Pathway and Steroidogenic Factor 1 in the Activation of the Mullerian Inhibiting Substance Type II Receptor

Synergistic Cooperation between the β-Catenin Signaling Pathway and Steroidogenic Factor 1 in the Activation of the Mullerian Inhibiting Substance Type II Receptor

PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

Functional localization and competition between the androgen receptor and T-cell factor for nuclear β-catenin: a means for inhibition of the Tcf signaling axis

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