A Coregulatory Role for the TRAP-Mediator Complex in Androgen Receptor-mediated Gene Expression

Wang, Qianben; Sharma, Dipali; Ren, Yunsheng; Fondell, Joseph D.

doi:10.1074/jbc.m206061200

Cited by 91 publications

(85 citation statements)

References 51 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although these studies clearly implicate functional interactions between AR and MED1, their respective binding domains have surprisingly remained poorly defined. Previous reports suggested that the two signature MED1 LXXLL motifs facilitate a very weak interaction with an isolated GST-AR AF2 fusion (9,32), yet the physiological relevance of these data is unclear in light of the much stronger N/C interaction that takes place between the AR N-terminal 23 FQNLF 27 motif and its core AF2 domain.…”

Section: Fqnlfmentioning

confidence: 90%

“…Transfer vectors baculovirusexpressing for HA-MED1-wt, -C⌬454, -C⌬690, -C⌬918, -C⌬1215, -ERK mutant (T1032A and T1457A), and full-length FLAG-AR were generated by subcloning the corresponding epitope-tagged open reading frames into plasmids pAcSG2 or pVL1392 (BD Biosciences). The androgen-responsive MMTVLuc reporter gene was reported earlier (32). The pMCL-HA-MKK1-8E and pMCL-HA-MKK1-N⌬4 expression vectors (38) and pCMV-ERK2-L73P/S151D expression vector (39) were provided by Natalie Ahn (University of Colorado).…”

Section: Methodsmentioning

confidence: 99%

“…Recombinant Baculovirus Protein Expression in Sf9 CellsGeneration of recombinant baculovirus and purification of recombinant proteins from infected Sf9 cells were carried out as previously described (27,32) with the exception that the FLAG-AR-infected Sf9 cells were additionally cultured and purified in the presence or absence of 10 nM DHT.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of Androgen Receptor-dependent Transcription by Coactivator MED1 Is Mediated through a Newly Discovered Noncanonical Binding Motif

Jin¹,

Claessens

Fondell³

2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: MED1 is a key coactivator for androgen receptor (AR)-dependent transcription in prostate cancer cells. Results: The mechanisms and binding motifs through which the MED1-Mediator complex functionally interact with AR were determined. Conclusion: MED1 functionally interacts with the Tau-1 domain of AR via a newly discovered noncanonical binding motif. Significance: Our findings provide new insights into the molecular mechanisms of AR-mediated transcriptional activation in prostate cancer cells.

show abstract

Section: Fqnlfmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of Androgen Receptor-dependent Transcription by Coactivator MED1 Is Mediated through a Newly Discovered Noncanonical Binding Motif

Jin¹,

Claessens

Fondell³

2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…By contrast, TRAP220 failed to enhance ER␣-mediated transcription of the 3ERE-TATA-LUC reporter gene (Fig 1B). Nonetheless, chromatin immunoprecipitation experiments have suggested that TRAP/DRIP proteins are recruited to NR-regulated promoters, including ER␣-and AR-responsive promoters (51,55,56), and microinjection of HeLa cell nuclei with anti-TRAP220/PBP antibodies down-regulated ER␣ activation of a reporter gene (57). In addition, a recent report has shown that the TRAP complex can be purified from HeLa cell nuclear extracts using GST-ER␣ LBD in the presence of agonist ligand (50).…”

Section: Trap220 Nuclear Receptor Binding Specificitymentioning

confidence: 99%

An Extended LXXLL Motif Sequence Determines the Nuclear Receptor Binding Specificity of TRAP220

Coulthard¹,

Matsuda

Heery

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The interaction of coactivators with the ligand-binding domain of nuclear receptors (NRs) is mediated by amphipathic ␣-helices containing the signature motif LXXLL. TRAP220 contains two LXXLL motifs (LXM1 and LXM2) that are required for its interaction with NRs. Here we show that the nuclear receptor interaction domain (NID) of TRAP220 interacts weakly with Class I NRs. In contrast, SRC1 NID binds strongly to both Class I and Class II NRs. Interaction assays using nine amino acid LXXLL core motifs derived from SRC1 and TRAP220 revealed no discriminatory NR binding preferences. However, an extended LXM1 sequence containing amino acids ؊4 to ؉9, (where the first conserved leucine is ؉1) showed selective binding to thyroid hormone receptor and reduced binding to estrogen receptor. Replacement of either TRAP220 LXXLL motif with the corresponding 13 amino acids of SRC1 LXM2 strongly enhanced the interaction of the TRAP220 NID with the estrogen receptor. Mutational analysis revealed combinatorial effects of the LXM1 core and flanking sequences in the determination of the NR binding specificity of the TRAP220 NID. In contrast, a mutation that increased the spacing between TRAP220 LXM1 and LXM2 had little effect on the binding properties of this domain. Thus, a 13-amino acid sequence comprising an extended LXXLL motif acts as the key determinant of the NR binding specificity of TRAP220. Finally, we show that the NR binding specificity of full-length TRAP220 can be altered by swapping extended LXM sequences.

show abstract

“…PGC-1β is an inducible coactivator of nuclear hormone receptors, which modulate metabolism via the Mediator complex (25,(40)(41)(42)(43). MED13, a regulatory subunit of the Mediator complex, is a predicted target of miR-378*.…”

mentioning

confidence: 99%

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Carrer

Liu²,

Grueter

et al. 2012

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

263

View full text Add to dashboard Cite

Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.fatty acid oxidation | adipocytes | mitochondrial CO 2 production

show abstract

A Coregulatory Role for the TRAP-Mediator Complex in Androgen Receptor-mediated Gene Expression

Cited by 91 publications

References 51 publications

Regulation of Androgen Receptor-dependent Transcription by Coactivator MED1 Is Mediated through a Newly Discovered Noncanonical Binding Motif

Regulation of Androgen Receptor-dependent Transcription by Coactivator MED1 Is Mediated through a Newly Discovered Noncanonical Binding Motif

An Extended LXXLL Motif Sequence Determines the Nuclear Receptor Binding Specificity of TRAP220

Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*

Contact Info

Product

Resources

About