Coactivator and corepressor complexes in nuclear receptor function

Xu, Lan; Glass, Christopher K.; Rosenfeld, Michael G.

doi:10.1016/s0959-437x(99)80021-5

Cited by 865 publications

(668 citation statements)

References 51 publications

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“…Most of the ERa coactivators binding to the AF-2 region of ERa have been shown to increase ERa transcriptional activity in a ligand-dependent manner. Recently, a few coactivators interact with the AF-1 or DBD region and regulate ERa transcriptional activity in a ligand-independent manner (Chakravarti et al, 1996;Yao et al, 1996;Weigel and Zhang, 1998;Alen et al, 1999;Endoh et al, 1999;Xu et al, 1999;Ding et al, 2003). Given that c-Abl does not interact with ERa P79,333A, the ligand-independent ERa transactivation by c-Abl seems to involve the AF-1 and AF-2 domains, especially the AF1 domain.…”

Section: Discussionmentioning

confidence: 99%

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

He¹,

Zheng²,

Song³

et al. 2010

Oncogene

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Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligandactivated transcription factors. Similar to other steroid hormone receptors, estrogen receptor a (ERa) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERa associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERa and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERa can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERa phosphorylation by c-Abl stabilizes ERa, resulting in enhanced ERa transcriptional activity and increased expression of endogenous ERa target genes. Furthermore, ERa phosphorylation at the Y-219 site affects DNA binding and dimerization by ERa. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Ablinduced accumulation of ERa and enhancement of ERa transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERa function. Moreover, the ERa (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERa expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.

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Section: Discussionmentioning

confidence: 99%

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

He¹,

Zheng²,

Song³

et al. 2010

Oncogene

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“…Nuclear receptors such as the farnesoid X receptor (NR1H4) and the thyroid hormone receptor heterodimerize with retinoid X receptors (RXR), of which RXRG is one of three family members, to bind to DNA response elements. 50 Depending on ligand availability, the nuclear receptor heterodimer associates with repressors or co-activators, 51 influencing chromatin structure by helicase-like domain carrying proteins (SMARCA2 and SMARCA4 52 ), by mediation of histone deacetylation (NCOR2 53 ), by p160 mediated histone acetylation (NCOA2 54 ) and by bridging histone acetylation activity with the transcription mediator complex (TGS1 55 ). The latter, that is bridging of histone acetylation and transcription mediation, is combined with tissue specificity in PPAR gamma co-activators, with PPARGC1B as one of the three family members.…”

Section: Discussionmentioning

confidence: 99%

Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study

et al. 2009

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Background: As nuclear receptors and transcription factors have an important regulatory function in adipocyte differentiation and fat storage, genetic variation in these key regulators and downstream pathways may be involved in the onset of obesity. Objective: To explore associations between single nucleotide polymorphisms (SNPs) in candidate genes from regulatory pathways that control fatty acid and glucose metabolism, and repeated measurements of body mass index (BMI) and waist circumference in a large Dutch study population. Methods: Data of 327 SNPs across 239 genes were analyzed for 3575 participants of the Doetinchem cohort, who were examined three times during 11 years, using the Illumina Golden Gate assay. Adjusted random coefficient models were used to analyze the relationship between SNPS and obesity phenotypes. False discovery rate q-values were calculated to account for multiple testing. Significance of the associations was defined as a q-value p0.20. Results: Two SNPs (in NR1H4 and SMARCA2 in women only) were significantly associated with both BMI and waist circumference. In addition, two SNPs (in SIRT1 and SCAP in women only) were associated with BMI alone. A functional SNP, in IL6, was strongly associated with waist. Conclusion: In this explorative study among participants of a large population-based cohort, five SNPs, mainly located in transcription mediator genes, were strongly associated with obesity phenotypes. The results from whole genome and candidate gene studies support the potential role of NR1H4, SIRT1, SMARCA2 and IL6 in obesity. Although replication of our findings and further research on the functionality of these SNPs and underlying mechanism is necessary, our data indirectly suggest a role of GATA transcription factors in weight control.

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“…Met is a member of the bHLH family of transcription factors . It was known that members of the bHLH family can form heterodimers with other PAS proteins (Ponting and Aravind, 1997) or with nuclear receptor proteins (Xu et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The bHLH domain is located near the N-terminus and this domain allows these proteins to form hetero or homodimers. The bHLH domain is followed by PAS-1 and PAS-2 domains which are involved in dimerization between PAS proteins (Heery et al, 1997) and non-PAS proteins (Xu et al, 1999) and these also help in binding to small molecules. The Met gene product is not vital as shown by the production of null mutants that are viable .…”

Section: Introductionmentioning

confidence: 99%

Interaction of proteins involved in ecdysone and juvenile hormone signal transduction

Bitra

Palli

2008

Arch Insect Biochem Physiol

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Ecdysteroids and juvenile hormones (JH) regulate a variety of developmental, physiological, behavioral, and metabolic processes. Ecdysteroids function through a heterodimeric complex of two nuclear receptors, ecdysone receptor (EcR) and ultraspiracle (USP). An 85 kDa protein identified in Drosophila melanogaster methoprene‐tolerant (Met) mutant binds to JH III with high affinity, and the mutant flies are resistant to juvenile hormone analog (JHA), methoprene. Reporter assays using the yeast two‐hybrid system were performed in order to study the molecular interactions between EcR, USP and Met. As expected, EcR fused to the B42 activation domain and USP fused to the LexA DNA binding domain interacted with each other and supported induction of the reporter gene in the presence of stable ecdysteroid analog, RG‐102240 or steroids, muristerone A and ponasterone A. The USP:USP homodimers supported expression of the reporter gene in the absence of ligand, and there was no significant increase in the reporter activity after addition of a JHA, methoprene. Similarly, Met:Met homodimers as well as Met:EcR and Met:USP heterodimers induced reporter activity in the absence of ligand and addition of ecdysteroid or JH analogs did not increase the reporter activity regulated by either homodimers or heterodimers of Met protein. Two‐hybrid assays in insect cells and in vitro pull‐down assays confirmed the interaction of Met with EcR and USP. These data suggest that the proteins that are involved in signal transduction of ecdysteroids (EcR and USP) and juvenile hormones (Met) interact to mediate cross‐talk between these two important hormones. Arch. Insect Biochem. Physiol. 2008. © 2008 Wiley‐Liss, Inc.

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Coactivator and corepressor complexes in nuclear receptor function

Cited by 865 publications

References 51 publications

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study

Interaction of proteins involved in ecdysone and juvenile hormone signal transduction

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