A Testis-specific Androgen Receptor Coregulator That Belongs to a Novel Family of Nuclear Proteins

Moilanen, Anu-Maarit; Karvonen, Ulla; Poukka, Hetti; Yan, Wei; Toppari, Jorma; Jänne, Olli A.; Palvimo, Jorma J.

doi:10.1074/jbc.274.6.3700

Cited by 144 publications

(134 citation statements)

References 25 publications

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“…These PIAS proteins influence AR-dependent transcription. Furthermore, PIAS1 and ARIP3/PIASx␣ are highly expressed in the testis (26,27). These findings raise the possibility that PIAS1 and ARIP3/ PIASx␣ may function as SUMO-E3 ligases toward the AR.…”

mentioning

confidence: 65%

“…The liganddependent sumoylation of hAR in intact cells may be explained, at least in part, by the translocation of the receptor into the nucleus. The AR must be transferred into the nucleus to become sumoylated because PIAS proteins are localized exclusively in the nucleus (23,27,32,33). 2 Further experiments are needed to define whether ligand binding facilitates the interaction of the receptor with PIAS proteins and to determine the physiological consequence of sumoylation besides the accumulation of ARs in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…PIAS1 was shown to interact with the AR (26). Rat ARIP3 (androgen receptor interacting protein 3), a protein found to bind to AR (27), is an ortholog of human PIASx␣. These PIAS proteins influence AR-dependent transcription.…”

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confidence: 99%

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PIAS1 and PIASxα Function as SUMO-E3 Ligases toward Androgen Receptor and Repress Androgen Receptor-dependent Transcription

Nishida¹,

Yasuda²

2002

Journal of Biological Chemistry

194

168

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The androgen receptor (AR)1 belongs to the steroid hormone nuclear receptor superfamily (1). The AR remains in the cytoplasm until it is activated by ligand binding. Upon ligand binding, this receptor dissociates from its heat-shock protein chaperones, becomes dimerized, and is translocated into the nucleus where it binds to specific androgen response elements (AREs) to regulate, along with other transcription factors, the transcription of its target genes. The AR plays important roles in male sexual development, prostate cell proliferation, and the progression of prostate cancer.The AR has been shown to be modified by small ubiquitinlike modifier 1, SUMO-1 (sumoylation), in vivo (2). Lysine residues at amino acid positions 386 and 520 of the human AR (hAR) are major sumoylation sites. Mutation of these residues blocks sumoylation and increases the transactivation ability of AR, suggesting that SUMO modification negatively regulates AR activity. However, the precise function of the sumoylation of AR remains unknown. Also SUMO-E3 ligase toward AR has not been identified.SUMO-1 has been shown to conjugate to target proteins through an isopeptide linkage between a glycine residue in the terminus and the ⑀-amino group of a lysine residue of the target protein. Sumoylation has multiple functions that include involvement in protein targeting, stabilization, and transcriptional regulation. Sumoylation of RanGAP1 results in movement of the protein from the cytoplasm to the nuclear pore complex (3-5). In the case of PML (promyelocytic leukemia) proteins, sumoylation regulates their subnuclear localization to structures termed PML nuclear bodies (6 -9). Sumoylation of inhibitor of B␣ acts antagonistically to ubiquitinylation and protects the sumoylated molecule itself from ubiquitin-mediated proteolysis (10). In addition, sumoylation of p53 has been proposed to regulate the transcriptional activity of p53 (11,12).Sumoylation of target proteins seems to occur in a manner analogous to the ubiquitinylation reaction. Heterodimeric E1 enzyme (Sua1/Uba2) and E2 enzyme (Ubc9) have already been detected by us and by other groups (13-18), and recently we identified PIAS1 as a SUMO-E3 ligase toward p53 (19). Also, we and other groups have shown yeast Siz1/Ull1 protein to have 21). PIAS1 and Siz1/Ull1 share significant homology in their critical RING finger-like domain (SP-RING) (22). More recently, PIASy was shown to markedly stimulate the sumoylation of LEF1 and multiple other proteins in vivo and to function as a SUMO-E3 ligase toward LEF1 in vitro (23). PIAS1 and PIAS3 were originally discovered as transcriptional co-regulators of the Janus kinase-STAT pathway (24,25). The human PIAS family consists of several homologous proteins, including PIAS1, PIAS3, PIASx␣, PIASx␤, PIASy, and a hypothetical protein (GenBank TM accession no. CAB66507); and all of them have a RING finger-like domain, where two consensus cysteine residues for the family seem to have been replaced by serine and asparatic acid (19,24,25). PIAS proteins interact ...

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confidence: 65%

Section: Discussionmentioning

confidence: 99%

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PIAS1 and PIASxα Function as SUMO-E3 Ligases toward Androgen Receptor and Repress Androgen Receptor-dependent Transcription

Nishida¹,

Yasuda²

2002

Journal of Biological Chemistry

194

168

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“…In contrast, PIASy represses STAT1, LEF1, Smad4 and the AR without interfering with DNA binding by these proteins (3,24,26,27). The Piasx gene encodes two splice variants, x␣ (ARIP3) and x␤ (Miz1), which interact with the AR and with the homeodomain protein Msx2, respectively (28,29). In addition, PIASx␤ interacts with STAT4, following IL-12 stimulation of T cells (5).…”

Section: Piasy-deficient Mice Display Modest Defects In Ifn Andmentioning

confidence: 99%

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

Roth

Sustmann

Kieslinger

et al. 2004

The Journal of Immunology

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Protein inhibitors of activated STATs (PIAS) represent a small family of nuclear proteins that modulate the activity of many transcription factors and act as E3 ligases for covalent modification of proteins with the small ubiquitin-like modifier (SUMO). In particular, PIASy has been shown to inhibit the activation of gene expression by the IFN-responsive transcription factor STAT1 and the Wnt-responsive transcription factor LEF1. To assess the function of PIASy in vivo, we generated and analyzed mice carrying a targeted mutation of the Piasy gene. We find that homozygous mutant mice have no obvious morphological defects and have a normal distribution of lymphocyte populations. Molecular analysis of signaling in response to IFN-γ and Wnt agonists revealed a modest reduction in the activation of endogenous and transfected target genes. Two-dimensional analysis of total proteins and SUMO-modified proteins in transformed pre-B cells showed no significant differences between wild-type mice and homozygous mutant mice. Taken together, our data indicate that PIASy has a modest effect on cytokine and Wnt signaling, suggesting a redundancy with other members of the family of PIAS proteins.

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“…PIASx␣ and PIASx␤ are probably derived from alternatively spliced mRNA products of the same gene. PIASx␣ interacts with the androgen receptor and regulates its activity (27,28). PIASx␤ interacts with the homeodomain protein Msx2 (29).…”

mentioning

confidence: 99%

Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT

Jiang

Matsuura

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

106

120

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A Testis-specific Androgen Receptor Coregulator That Belongs to a Novel Family of Nuclear Proteins

Cited by 144 publications

References 25 publications

PIAS1 and PIASxα Function as SUMO-E3 Ligases toward Androgen Receptor and Repress Androgen Receptor-dependent Transcription

PIAS1 and PIASxα Function as SUMO-E3 Ligases toward Androgen Receptor and Repress Androgen Receptor-dependent Transcription

PIASy-Deficient Mice Display Modest Defects in IFN and Wnt Signaling

Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT

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