Dimerization modulates the activity of the orphan nuclear receptor ERRγ

Huppunen, Johanna; Aarnisalo, Piia

doi:10.1016/j.bbrc.2003.12.194

Cited by 73 publications

(49 citation statements)

References 31 publications

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“…Furthermore, it has previously been reported that heterodimerization between NRs sometimes inhibits receptor activity. For example, heterodimerization between ERRg and ERRa was found to inhibit the transcriptional activities of both receptors (40). Results of the present study suggest another possible mechanism where ERh2 induces proteasome-dependent degradation of ERa, resulting in limiting levels of this protein, thus leading to suppression of ERa transcriptional activity.…”

Section: Discussionmentioning

confidence: 51%

Estrogen Receptor β2 Negatively Regulates the Transactivation of Estrogen Receptor α in Human Breast Cancer Cells

et al. 2007

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Estrogens, by binding to and activating two estrogen receptors (ERA and ERB), are critically involved in the development of the mammary gland and breast cancer. An isoform of ERB, ERB2 (also called ERBcx), with an altered COOH-terminal region, is coexpressed with ERA in many human breast cancers. In this study, we generated a stable cell line from MCF7 breast cancer cells expressing an inducible version of ERB2, along with endogenous ERA, and examined the effects of ERB2 on the ERA protein levels and function. We showed that ERB2 inhibited ERA-mediated transactivation via estrogen response element and activator protein-1 sites of reporter constructs as well as the endogenous genes pS2 and MMP-1. Chromatin immunoprecipitation assays revealed that ERB2 expression caused a significant reduction in the recruitment of ERA to both the pS2 and MMP-1 promoters. Furthermore, ERB2 expression induced proteasome-dependent degradation of ERA. The inhibitory effects of ERB2 on ERA activity were further confirmed in HEK293 cells that lack functional endogenous ERs. We also showed that ERB2 can interact with ERA both in vitro and in mammalian cells, which is compatible with a model where ERB2/ERA heterodimers are targeted to the proteasome. Finally, in human breast cancer samples, we observed that expression of ERB2 significantly correlated with ERA-negative phenotype. Our data suggest that ERB2 could influence ERA-mediated effects relevant for breast cancer development, including hormone responsiveness. [Cancer Res 2007;67(8):3955-62]

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Section: Discussionmentioning

confidence: 51%

Estrogen Receptor β2 Negatively Regulates the Transactivation of Estrogen Receptor α in Human Breast Cancer Cells

et al. 2007

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“…However, ERR␣ did not affect the FSK-stimulated DNA binding ability of ERR␥ on Pck1 ERREs. Similarly, it has been shown that ERR␣ can inhibit ERR␥ transcriptional activity without affecting the DNA binding ability of ERR␥ and suggested that a mechanism for ERR␣ repression is the heterodimerization between the ERRs as evidenced by the reports showing that heterodimerization between ERR␣ and ERR␥ inhibits transactivation of each other, whereas homodimerization is needed for their transcriptional activity (32,48,49). On the other hand, their functions in terms of transcriptional regulation of each ERR for downstream targets are more complicated.…”

Section: Discussionmentioning

confidence: 99%

Orphan Nuclear Receptor Estrogen-Related Receptor γ (ERRγ) Is Key Regulator of Hepatic Gluconeogenesis

Kim

Ryu

Koh

et al. 2012

Journal of Biological Chemistry

120

138

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Background: Dysregulation of glucose homeostasis is often associated with insulin resistance and diabetes. Results: Hepatic ERR␥ expression is increased by fasting-dependent activation of the CREB-CRTC2 pathway, which leads to the induction of hepatic gluconeogenesis. Conclusion: Orphan nuclear receptor ERR␥ is a novel transcriptional regulator of hepatic gluconeogenesis. Significance: An ERR␥ inverse agonist could be a new potential therapeutic approach for the treatment of type 2 diabetes.

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“…It has been documented that DNA binding and dimerization influence the transcriptional properties of ERRs (26,40,49,50). PGC-1␣, for example, has been reported to bind only to ERR␣ homodimers, the formation of which depends on the exact sequence of the DNAbinding site and phosphorylation of the DNA-binding domain (26,40,49,50).…”

Section: Discussionmentioning

confidence: 99%

Communication between the ERRα Homodimer Interface and the PGC-1α Binding Surface via the Helix 8–9 Loop

Greschik

Althage

Flaig

et al. 2008

Journal of Biological Chemistry

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Although structural studies on the ligand-binding domain (LBD) have established the general mode of nuclear receptor (NR)/coactivator interaction, determinants of binding specificity are only partially understood. The LBD of estrogen receptor-␣ (ER␣), for example, interacts only with a region of peroxisome proliferator-activated receptor coactivator (PGC)-1␣, which contains the canonical LXXLL motif (NR box2), whereas the LBD of estrogen-related receptor-␣ (ERR␣) also binds efficiently an untypical, LXXYL-containing region (NR box3) of PGC-1␣. Surprisingly, in a previous structural study, the ER␣ LBD has been observed to bind NR box3 of transcriptional intermediary factor (TIF)-2 untypically via LXXYL, whereas the ERR␣ LBD binds this region of TIF-2 only poorly. Here we present a new crystal structure of the ERR␣ LBD in complex with a PGC-1␣ box3 peptide. In this structure, residues N-terminal of the PGC-1␣ LXXYL motif formed contacts with helix 4, the loop connecting helices 8 and 9, and with the C terminus of the ERR␣ LBD. Interaction studies using wild-type and mutant PGC-1␣ and ERR␣ showed that these contacts are functionally relevant and are required for efficient ERR␣/PGC-1␣ interaction. Furthermore, a structure comparison between ERR␣ and ER␣ and mutation analyses provided evidence that the helix 8 -9 loop, which differs significantly in both nuclear receptors, is a major determinant of coactivator binding specificity. Finally, our results revealed that in ERR␣ the helix 8 -9 loop allosterically links the LBD homodimer interface with the coactivator cleft, thus providing a plausible explanation for distinct PGC-1␣ binding to ERR␣ monomers and homodimers.

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Dimerization modulates the activity of the orphan nuclear receptor ERRγ

Cited by 73 publications

References 31 publications

Estrogen Receptor β2 Negatively Regulates the Transactivation of Estrogen Receptor α in Human Breast Cancer Cells

Estrogen Receptor β2 Negatively Regulates the Transactivation of Estrogen Receptor α in Human Breast Cancer Cells

Orphan Nuclear Receptor Estrogen-Related Receptor γ (ERRγ) Is Key Regulator of Hepatic Gluconeogenesis

Communication between the ERRα Homodimer Interface and the PGC-1α Binding Surface via the Helix 8–9 Loop

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