Monomeric Complex of Human Orphan Estrogen Related Receptor-2 with DNA: A Pseudo-dimer Interface Mediates Extended Half-site Recognition

Gearhart, Micah D.; Holmbeck, S. M. A.; Evans, Ronald M.; Dyson, H. Jane; Wright, Peter E.

doi:10.1016/s0022-2836(03)00183-9

Cited by 97 publications

(82 citation statements)

References 56 publications

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“…In contrast to the hLRH-1 crystal structure, the F/J angles of the glycine residues in the RGGR motif in the hERR2 solution structures are not in glycine-only regions of Ramachandran space. 32 However, the arginine side-chains in the hERR2 structures align well with those observed in the hLRH-1 crystal structure (Figure 3(d)). These observations indicate that LRH-1 and ERR2 both appear to recognize 5 0 -YCA extensions using similar DNA-specific contacts and the RGGR motif.…”

Section: Comparison With Other Monomeric Nr Dbdssupporting

confidence: 71%

“…The structure contains the core dual Cys 4 -type Zn module domain of the hLRH-1 DBD (residues 84-151), the CTE (152-167), and 11 out of 20 residues of the Ftz-F1 domain (168-178) (Figure 1(a) and (b)). The core domain is similar to that of other NR DBDs, [25][26][27][28][29][30][31][32] and positions an a-helix in the major groove of the AGGCCA sequence of the DNA (Figure 1(b)). The CTE extends into the minor groove and contacts the TCA extension located 5 0 to the canonical hexameric sequence bound by NRs (Figure 1(b)).…”

Section: Resultsmentioning

confidence: 59%

“…It has been shown in the solution structures of the hERR2 DBD, another monomeric NR, that the CTE of this receptor was disordered without DNA but becomes ordered upon DNA binding. 32 Thus, it is likely that NR5A receptor CTEs are also somewhat disordered in the absence of DNA. For hLRH-1, we show that mutations disrupting the orientation of the Ftz-F1 helix adjacent to the DBD do not affect DNA-binding affinity (K d ; Table 2; Figures 4(b) and 5(a)), which indicates that the aromatic residues that pack the Ftz-F1 helix against the DBD are not strictly required for DNA binding.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Solomon

Hager

Safi

et al. 2005

Journal of Molecular Biology

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Section: Comparison With Other Monomeric Nr Dbdssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Solomon

Hager

Safi

et al. 2005

Journal of Molecular Biology

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“…5A) in the context of a Nanog promoter-luciferase construct. Nuclear magnetic resonance structural analysis of the Esrrb DNA binding domain in complex with DNA shows that these bases make a major contribution to DNA binding by Esrrb (10). This mutation strongly reduced Nanog promoter activity (Fig.…”

Section: Downloaded Frommentioning

confidence: 98%

Estrogen-Related Receptor Beta Interacts with Oct4 To Positively Regulate Nanog Gene Expression

Berg

Zhang

Yates

et al. 2008

Molecular and Cellular Biology

148

122

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Embryonic stem (ES) cell self-renewal is regulated by transcription factors, including Oct4, Sox2, and Nanog. A number of additional transcriptional regulators of ES cell self-renewal have recently been identified, including the orphan nuclear receptor estrogen-related receptor beta (Esrrb). However, the mode of action of Esrrb in ES cells is unknown. Here, using an Oct4 affinity screen, we identify Esrrb as an Oct4 partner protein. Esrrb can interact with Oct4 independently of DNA. Esrrb is recruited near the Oct-Sox element in the Nanog proximal promoter, where it positively regulates Nanog expression. Esrrb recruitment to the Nanog promoter requires both the presence of Oct4 and a degenerate estrogen-related receptor DNA element. Consistent with its role in Nanog regulation, expression of the Esrrb protein within the Oct4-positive ES cell population is mosaic and correlates with the mosaic expression of the Nanog protein. Together with previous reports that Nanog may regulate Esrrb gene expression, our results suggest that Esrrb and Nanog act as part of a feedback regulatory circuit that modulates the fluctuating self-renewal capacity of ES cell populations.The self-renewal of mouse ES cells is regulated by a network of transcription factors that includes Oct4, Nanog, and Sox2 (22). The expression level of Oct4 protein needs to be kept within a tight range in order to maintain ES cell self-renewal (23). Decreasing Oct4 levels below 50% induces differentiation into the trophectoderm, whereas a twofold increase causes differentiation into cells expressing markers of the endoderm and mesoderm (23). In contrast, overexpression of Nanog allows mouse embryonic stem (ES) cells to remain undifferentiated in the absence of the otherwise requisite stimulation by leukemia inhibitory factor and bone morphogenetic protein (5,19,34). Oct4 is thought to act together with Sox2 by binding to adjacent cognate DNA sequences in many genes (1), including Nanog (14, 26). Genome-wide chromatin immunoprecipitation (ChIP) studies have suggested that composite Oct-Sox motifs regulate the expression of many genes in mouse and human ES cells (2, 16). Recent evidence has shown that the critical role of Sox2 in maintaining ES cell self-renewal is regulating Oct4 expression, suggesting that the secondary role of gene regulation via Oct-Sox motifs is performed redundantly with Sox4, Sox11, and Sox15 (18).Recent reports have expanded the list of factors that contribute to ES cell self-renewal. Wang et al. (30) reported a proteomic analysis of interactors of Oct4 and Nanog and suggested that some Nanog interactors may assist in Nanogmediated gene regulation. A separate study using an RNA interference (RNAi) screen found that depletion of estrogenrelated receptor beta (Esrrb), Tbx3, or Tcl1 resulted in ES cell differentiation but that this differentiation could be attenuated by overexpression of Nanog (13). However, it is unclear how any of these novel regulatory factors mediate their function. Here we use an unbiased analysis of Oct4 binding...

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“…1). ERRa is functionally similar to ERa in that it can bind the inverted repeat estrogen response element (ERE) sequence in target gene promoters, although ERRa preferentially binds a ninenucleotide extended half site sequence, the ERRE (2)(3)(4). In contrast to the ligand-dependent activation of ERa, ERRa is constitutively active and does not respond to estradiol or other natural estrogens (1,5), although its activity can be inhibited by the synthetic estrogen diethylstilbestrol (6,7).…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor–Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor α

Barry

Giguère

2005

Cancer Research

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The orphan nuclear hormone receptor estrogen-related receptor A (ERRA, NR3B1) is a constitutive transcription factor that is structurally and functionally related to the classic estrogen receptors. ERRA can recognize both the estrogen response element and its own binding site (ERRE) in either dimeric or monomeric forms. ERRA is also a phosphoprotein whose expression in human breast tumors correlates with that of the receptor tyrosine kinase ErbB2, suggesting that its transcriptional activity could be regulated by signaling cascades. Here, we investigated growth factor regulation of ERRA function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding. Interestingly, treatment with alkaline phosphatase shifts ERRA from a dimeric to a monomeric DNA-binding factor, and only the dimeric form interacts with the coactivator PGC-1A. In vitro, the DNA-binding domain of ERRA is selectively phosphorylated by protein kinase CD (PKCD), which increases its DNA-binding activity, whereas expression of constitutively active PKCD enhances TFF1 promoter activity via the ERRE. However, whereas treatment of MCF-7 cells with the phorbol ester phorbol-12-myristate 13-acetate also enhances ERRA activation of the TFF1 promoter reporter, it does not affect ERRA activity on its own promoter. In agreement, chromatin immunoprecipitation analysis shows that ERRA and RNA polymerase II are preferentially recruited to the TFF1 promoter after EGF treatment, whereas recruitment of these factors to its own promoter is not affected. These results reveal a mechanism through which growth factor signaling can selectively activate ERRA target genes in breast cancer cells. (Cancer Res 2005; 65(14): 6120-29)

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Monomeric Complex of Human Orphan Estrogen Related Receptor-2 with DNA: A Pseudo-dimer Interface Mediates Extended Half-site Recognition

Cited by 97 publications

References 56 publications

Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Estrogen-Related Receptor Beta Interacts with Oct4 To Positively Regulate Nanog Gene Expression

Epidermal Growth Factor–Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor α

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