Coregulator Small Nuclear RING Finger Protein (SNURF) Enhances Sp1- and Steroid Receptor-mediated Transcription by Different Mechanisms

Poukka, Hetti; Aarnisalo, Piia; Santti, Henrikki; Jänne, Olli A.; Palvimo, Jorma J.

doi:10.1074/jbc.275.1.571

Cited by 68 publications

(65 citation statements)

References 59 publications

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“…In addition, RNF4 is a transcriptional coregulator for members of the nuclear receptor superfamily that are sumoylated within their transcriptional inhibitory domains (Moilanen et al, 1998;Poukka et al, 2000b;AbdelHafiz et al, 2002;Tian et al, 2002). Interestingly, the residues of RNF4 that are required for its interaction with the androgen receptor (amino acids 31-65 (Poukka et al, 2000a)) encompass the SIMs that we identified. Furthermore, the SUMO and ubiquitin-dependent regulation of D. discoideum MEK1, an MAP kinase kinase required for chemotaxis, provides particularly compelling support for our model (Sobko et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

SUMO-targeted ubiquitin ligases in genome stability

Prudden

Pébernard

Raffa

et al. 2007

EMBO J

309

389

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We identify the SUMO-Targeted Ubiquitin Ligase (STUbL) family of proteins and propose that STUbLs selectively ubiquitinate sumoylated proteins and proteins that contain SUMO-like domains (SLDs). STUbL recruitment to sumoylated/SLD proteins is mediated by tandem SUMO interaction motifs (SIMs) within the STUbLs N-terminus. STUbL-mediated ubiquitination maintains sumoylation pathway homeostasis by promoting target protein desumoylation and/or degradation. Thus, STUbLs establish a novel mode of communication between the sumoylation and ubiquitination pathways. STUbLs are evolutionarily conserved and include: Schizosaccharomyces pombe Slx8-Rfp (founding member), Homo sapiens RNF4, Dictyostelium discoideum MIP1 and Saccharomyces cerevisiae Slx5-Slx8. Cells lacking Slx8-Rfp accumulate sumoylated proteins, display genomic instability, and are hypersensitive to genotoxic stress. These phenotypes are suppressed by deletion of the major SUMO ligase Pli1, demonstrating the specificity of STUbLs as regulators of sumoylated proteins. Notably, human RNF4 expression restores SUMO pathway homeostasis in fission yeast lacking Slx8-Rfp, underscoring the evolutionary functional conservation of STUbLs. The DNA repair factor Rad60 and its human homolog NIP45, which contain SLDs, are candidate STUbL targets. Consistently, Rad60 and Slx8-Rfp mutants have similar DNA repair defects.

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Section: Discussionmentioning

confidence: 99%

SUMO-targeted ubiquitin ligases in genome stability

Prudden

Pébernard

Raffa

et al. 2007

EMBO J

309

389

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“…RNF4 can interact with both DNA and proteins (transcription factors) and may promote an assembly of nucleoprotein structures (12). It has been shown that RNF4 modulates the transcriptional activities of androgen receptor and SP1 via different domains, and it may act as a functional link between steroidand SP1-regulated transcription (16). Moreover, it has been shown that RNF4 facilitates AR import to nuclei and retards its export on hormone withdrawal, suggesting that RNF4-me- diated tethering of AR in nuclei represents a novel mechanism for activating steroid receptor functions (27).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which RNF4 modulates androgen-dependent transcription have been investigated (12,14,16,26). RNF4 can interact with both DNA and proteins (transcription factors) and may promote an assembly of nucleoprotein structures (12).…”

Section: Discussionmentioning

confidence: 99%

“…RNF4 codes for a 21-kDa protein containing a RING finger motif (14,15) and associates with the DNA binding domain of AR to enhance transcriptional response to androgens (14). RNF4 also functions as a coactivator of SP1-regulated promoters (16). RNF4, in turn, associates with a variety of transcription factors (HMGI-Y, PATZ, gscl, SPBP) (17)(18)(19) probably by virtue of the RING finger, which is a domain specialized in the formation of protein complexes.…”

mentioning

confidence: 99%

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PATZ Attenuates the RNF4-mediated Enhancement of Androgen Receptor-dependent Transcription

Pero¹,

Lembo²,

Palmieri³

et al. 2002

Journal of Biological Chemistry

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PATZ is a transcriptional repressor affecting the basal activity of different promoters, whereas RNF4 is a transcriptional activator. The association of PATZ with RNF4 switches the activation to repression of selected basal promoters. Because RNF4 interacts also with the androgen receptor (AR) functioning as a coactivator and, in turn, RNF4 associates with PATZ, we investigated whether PATZ functions as an AR coregulator. We demonstrate that PATZ does not influence directly the AR response but acts as an AR corepressor in the presence of RNF4. Such repression is not dependent on histone deacetylases. A mutant RNF4 that does not bind PATZ but enhances AR-dependent transcription is not influenced by PATZ, demonstrating that the repression by PATZ occurs only upon binding to RNF4. We also demonstrate that RNF4, AR, and PATZ belong to the same complex in vivo also in the presence of androgen, suggesting that repression is not mediated by the displacement of RNF4 from AR. Finally, we show that the repression of endogenous PATZ expression by antisense expression plasmids in LNCaP cells results in a stronger androgen response. Our findings demonstrate that PATZ is a novel AR coregulator that acts by modulating the effect of a coactivator. This could represent a novel and more general mechanism to finely tune the androgen response.Androgens are critical in development, maintenance of the male reproductive system, and for growth of normal prostate and prostate cancer (1, 2). The effects of androgens are mediated through the androgen receptor (AR), 1 a member of a large family of ligand-dependent transcriptional factors that belongs to the steroid receptor superfamily (3, 4).AR can interact directly with basal transcription factors, such as TBP (5), TFIIB (6), and TFIIF (7). The activation of target gene expression by nuclear receptors is not just the result of ligand availability, but it is also tightly modulated by several coregulatory proteins, which function in many cases as signaling intermediates between receptors and general transcription or chromatin-modeling machineries. Coregulators interact with different regions of AR and can act as coactivators (e.g. SRC-1, CBP, ARA-70, ARA-54, SNURF/RNF4, ANPK, ARIP-3, ARIP-4, E6-AP) or corepressors (e.g. nuclear factor-B, SMAD3, D-type cyclins) (8 -13). However, the physiological significance of coregulators and their activating or repressing functions on AR-dependent transcription are still under investigation.One of the most recently described AR coactivators is RNF4/ SNURF (14). RNF4 codes for a 21-kDa protein containing a RING finger motif (14, 15) and associates with the DNA binding domain of AR to enhance transcriptional response to androgens (14). RNF4 also functions as a coactivator of SP1-regulated promoters (16). RNF4, in turn, associates with a variety of transcription factors (HMGI-Y, PATZ, gscl, SPBP) (17-19) probably by virtue of the RING finger, which is a domain specialized in the formation of protein complexes. Thus, RNF4 could function as an adapter protei...

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“…Since the PEST sequence in the AR hinge region overlaps the bipartite nuclear translocation region (19,26), it is possible that ubiquitination of AR in this region may provide the recognition site for proteasome association, resulting in the modulation of AR nuclear translocation. To support the role of the ubiquitin-proteasome pathway in AR nuclear translocation, it has been shown that the Snurf1 coregulator, a RING finger protein, could bind to the AR hinge region to enhance AR transactivation via promotion of AR nuclear translocation (19,42). However, it remains to be determined whether Snurf1 has intrinsic E3 ligase activity to ubiquitinate AR and allow proteasome recognition and thus promotion of AR nuclear translocation.…”

Section: Mg132 Inhibits the Interaction Between Ar And Ar Coregulators-mentioning

confidence: 99%

Proteasome Activity Is Required for Androgen Receptor Transcriptional Activity via Regulation of Androgen Receptor Nuclear Translocation and Interaction with Coregulators in Prostate Cancer Cells

Lin

Altuwaijri

Lin

et al. 2002

Journal of Biological Chemistry

130

111

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Upon binding to androgen, the androgen receptor (AR) can translocate into the nucleus and bind to androgen response element(s) to modulate its target genes. Here we have shown that MG132, a 26 S proteasome inhibitor, suppressed AR transactivation in an androgen-dependent manner in prostate cancer LNCaP and PC-3 cells. In contrast, MG132 showed no suppressive effect on glucocorticoid receptor transactivation. Additionally, transfection of PSMA7, a proteasome subunit, enhanced AR transactivation in a dose-dependent manner. The suppression of AR transactivation by MG132 may then result in the suppression of prostate-specific antigen, a well known marker used to monitor the progress of prostate cancer. Further mechanistic studies indicated that MG132 may suppress AR transactivation via inhibition of AR nuclear translocation and/or inhibition of interactions between AR and its coregulators, such as ARA70 or TIF2. Together, our data suggest that the proteasome system plays important roles in the regulation of AR activity in prostate cancer cells and may provide a unique target site for the development of therapeutic drugs to block androgen/AR-mediated prostate tumor growth.The ubiquitin-proteasome system degrades misfolded or unfolded proteins in order to control a variety of biological functions, including cell proliferation, differentiation, and stress response (1-3). The multicomplex 26 S proteasome contains two 19 S regulatory complexes and a 20 S catalytic core complex that may be responsible for 80 -90% of protein degradation in the cell (4). The 19 S complexes are responsible for recognition of the polyubiquitinated protein substrates and work to bridge the substrates to the 20 S core complex for degradation. The barrel-shaped 20 S complex contains four rings, each of which is made up of seven different subunits. The two outer rings contain ␣-type subunits, whereas the inner rings contain ␤-type subunits (4, 5). Several proteins involved in cell cycle regulation, like p27 and cyclin, are known to be degraded by the ubiquitin-proteosome pathway (6 -8). The protein ubiquitination is initiated by multiple enzyme reactions catalyzed by a single ubiquitin-activating enzyme (E1), a few ubiquitin-conjugating enzymes (E2s), 1 and a large variety of ubiquitin-protein ligases (E3s). The intrinsic E3 ligase activity represents the rate limiting step of ubiquitin modification of proteins. Therefore,thecontroloftheE3ligaseactivitymayinfluenceproteasome-dependent protein degradation (2, 5).Proteasomes are known to play an essential role in thymocyte apoptosis and inflammatory responses (9 -12). The proteasome inhibitors, such as MG132, suppress the inflammatory response by blocking NF-B activation or induction of heat shock protein expression, which may allow cells to resist higher temperatures and other toxic agents as well as prevent leukemia cell apoptosis (13-15). In contrast, proteasome inhibitors can also induce cancer cell apoptosis, accompanied by activation of several caspases, such as caspase-3 or caspase-7 (16, 17...

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Coregulator Small Nuclear RING Finger Protein (SNURF) Enhances Sp1- and Steroid Receptor-mediated Transcription by Different Mechanisms

Cited by 68 publications

References 59 publications

SUMO-targeted ubiquitin ligases in genome stability

SUMO-targeted ubiquitin ligases in genome stability

PATZ Attenuates the RNF4-mediated Enhancement of Androgen Receptor-dependent Transcription

Proteasome Activity Is Required for Androgen Receptor Transcriptional Activity via Regulation of Androgen Receptor Nuclear Translocation and Interaction with Coregulators in Prostate Cancer Cells

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