Functional Domains of Androgen Receptor Coactivator p44/Mep50/WDR77and Its Interaction with Smad1

Li, Yirong; Tian, Liantian; Ligr, Martin; Daniels, Garrett; Peng, Yi; Wu, Xinyu; Singh, Mandeep; Wei, Jian‐Jun; Shao, Yongzhao; Lepor, Herbert; Xu, Ruliang; Chen, Zhijie; Wang, Zhengxin; Lee, Peng

doi:10.1371/journal.pone.0064663

Cited by 6 publications

(4 citation statements)

References 27 publications

(37 reference statements)

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“…None of these studies detected direct interaction between AR and p53. Interaction between AR and WDR77 has been shown ( Li et al, 2013 ) and our studies show that WDR77 mediates recruitment of p53 to AR.…”

Section: Discussionsupporting

confidence: 71%

“…Despite previous reports of functional interaction between AR and p53 ( Dean and Knudsen, 2013 ; Guseva et al, 2012 ; Cronauer et al, 2004 ; Shenk et al, 2001 ; Gurova et al, 2002 ), these proteins have never been found to interact directly. However, interaction between WDR77 and AR has been described ( Li et al, 2013 ). Therefore, the possibility that p53 and WDR77 interact physically was explored.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

Liu

Kumari

et al. 2017

eLife

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Standard treatment for metastatic prostate cancer (CaP) prevents ligand-activation of androgen receptor (AR). Despite initial remission, CaP progresses while relying on AR. AR transcriptional output controls CaP behavior and is an alternative therapeutic target, but its molecular regulation is poorly understood. Here, we show that action of activated AR partitions into fractions that are controlled preferentially by different coregulators. In a 452-AR-target gene panel, each of 18 clinically relevant coregulators mediates androgen-responsiveness of 0–57% genes and acts as a coactivator or corepressor in a gene-specific manner. Selectivity in coregulator-dependent AR action is reflected in differential AR binding site composition and involvement with CaP biology and progression. Isolation of a novel transcriptional mechanism in which WDR77 unites the actions of AR and p53, the major genomic drivers of lethal CaP, to control cell cycle progression provides proof-of-principle for treatment via selective interference with AR action by exploiting AR dependence on coregulators.

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Section: Discussionsupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

Liu

Kumari

et al. 2017

eLife

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“…Consistent with this observation, overexpression of MEP50 in the nucleus stimulated proliferation and invasion only in the presence of estrogen or androgen [19]. Part of the role of MEP50 in hormone-responsive tumors may be independent of PRMT5, mediated through interaction and recruitment of the Smad1 transcription factor [16]. …”

Section: Introductionmentioning

confidence: 79%

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

Stopa

Krebs

Shechter

2015

Cell. Mol. Life Sci.

386

399

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Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5–MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5–MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymo-logical studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.

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“…P44/WDR77 has been identified as a coactivator of the AR, with distinct growth suppression and promotion function in gender-specific endocrine organs and their malignancies. Instead of the traditional WD40 domain at the C-terminus, it has been shown that the N-terminal region of p44 mediates the interaction between p44, the N-terminus of the AR, and full-length Smad1 (Li et al 2013). P44 is a component of the methylome complex (Friesen et al 2002) suggesting that it functions as a coactivator via supporting methylation (see Table 1).…”

Section: Journal Of Molecular Endocrinologymentioning

confidence: 99%

The role of WD40 repeat-containing proteins in endocrine (dys)function

Bruinstroop

Hollenberg

et al. 2023

Journal of Molecular Endocrinology

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WD40 repeat-containing proteins play a key role in many cellular functions including signal transduction, protein degradation, and apoptosis. The WD40 domain is highly conserved, and its typical structure is a β-propeller consisting of 4-8 blades which probably serves as a scaffold for protein-protein interaction. Some WD40 repeat-containing proteins form part of the corepressor complex of nuclear hormone receptors, a family of ligand-dependent transcription factors that play a central role in the regulation of gene transcription. This explains their involvement in endocrine physiology and pathology. In the present review, we first touch upon the structure of WD40 repeat-containing proteins. Next, we describe our current understanding of the role of WD40 domain containing proteins in nuclear receptor signaling e.g. as corepressor or coactivator. In the final part of this review, we focus on WD40 domain containing proteins that are associated with endocrine pathologies. These pathologies vary from isolated dysfunction of one endocrine axis, e.g., congenital isolated central hypothyroidism, to more complex congenital syndromes comprising endocrine phenotypes, such as the Triple-A syndrome.

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Functional Domains of Androgen Receptor Coactivator p44/Mep50/WDR77and Its Interaction with Smad1

Cited by 6 publications

References 27 publications

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

The role of WD40 repeat-containing proteins in endocrine (dys)function

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