A Dynamic Balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and Retinoic Acid Receptor:Retinoid X Receptor Heterodimers Regulates Oct-3/4 Expression in Embryonal Carcinoma Cells

Ben-Shushan, Etti; Sharir, Hava; Pikarsky, Eli; Bergman, Yehudit

doi:10.1128/mcb.15.2.1034

Cited by 148 publications

(101 citation statements)

References 66 publications

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“…Several studies have demonstrated that the carboxy termini of COUP-TFs represent a transferable active repression domain (6,10,18,31). To map the boundaries of this domain of ARP-1/COUP-TFII, various segments of its carboxy terminus were fused to the GAL4 DBD.…”

Section: Resultsmentioning

confidence: 99%

“…Members of the COUP-TF family preferentially form homodimers and bind to a wide variety of response elements, which are recognized by other members of the superfamily (11). Studies of members of the COUP-TF family in differentiated mammalian cells provide evidence for a role of these proteins in modulating transcriptional regulation of multiple genes by retinoid receptors (6,55,58), hepatocyte nuclear factor 4 (HNF-4) (17,25,41), vitamin D 3 receptor (10,11), thyroid hormone receptor (TR) (10,11), or peroxisome proliferator-activated receptor (43).…”

mentioning

confidence: 99%

“…The carboxy-termini of COUP-TFs have been defined as the active repression domain by several investigators (6,10,18,31). Ge and coworkers reported that the amino terminus of ARP-1/COUP-TFII harbors a second domain capable of repressing transcriptional activity of the human apo-AI gene promoter (18).…”

mentioning

confidence: 99%

“…As no specific ligand for these proteins has been identified so far, they are classified as orphan receptors. Members of the COUP-TF family are potent repressors of the transcriptional activities of multiple genes, including several apolipoprotein-encoding genes (25, 47-50, 55, 64, 65), the ␣-fetoprotein gene (32), the erythropoietin gene (17), the oxytocin gene (35,62), and numerous others (1,6,33,34). A considerable number of genes, such as the arrestin gene (36), the vHNF-1 gene (51), and the phosphoenolpyruvate carboxykinase gene (19), have been found to be activated by COUP-TFs.…”

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confidence: 99%

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Functional Domains of the Human Orphan Receptor ARP-1/ COUP-TFII Involved in Active Repression and Transrepression

Achatz¹,

Hölzl²,

Speckmayer³

et al. 1997

Molecular and Cellular Biology

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The orphan receptor ARP-1/COUP-TFII, a member of the chicken ovalbumin upstream promoter transcription factor (COUP-TF) subfamily of nuclear receptors, strongly represses transcriptional activity of numerous genes, including several apolipoprotein-encoding genes. Recently it has been demonstrated that the mechanism by which COUP-TFs reduce transcriptional activity involves active repression and transrepression. To map the domains of ARP-1/COUP-TFII required for repressor activity, a detailed deletion analysis of the protein was performed. Chimeric proteins in which various segments of the ARP-1/COUP-TFII carboxy terminus were fused to the GAL4 DNA binding domain were used to characterize its active repression domain. The smallest segment confering active repressor activity to a heterologous DNA binding domain was found to comprise residues 210 to 414. This domain encompasses the region of ARP-1/COUP-TFII corresponding to helices 3 to 12 in the recently published crystal structure of other members of the nuclear receptor superfamily. It includes the AF-2 AD core domain formed by helix 12 but not the hinge region, which is essential for interaction with a corepressor in the case of the thyroid hormone and retinoic acid receptor. Attachment of the nuclear localization signal from the simian virus 40 large T antigen (Flu tag) to the amino terminus of ARP-1/COUP-TFII abolished its ability to bind to DNA without affecting its repressor activity. By using a series of Flu-tagged mutants, the domains required for transrepressor activity of the protein were mapped.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Functional Domains of the Human Orphan Receptor ARP-1/ COUP-TFII Involved in Active Repression and Transrepression

Achatz¹,

Hölzl²,

Speckmayer³

et al. 1997

Molecular and Cellular Biology

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“…Oct-3/4 gene expression is regulated by RA through its enhancer and promoter elements (3,38,41,45,54,66,74). Whereas no RA-responsive elements (RARE) were identified in the enhancer region, the Oct-3/4 promoter contains a RARE motif (designated RAREoct) which contributes to transcriptional activation in EC cells and mediates the RAinduced repression in RA-differentiated EC cells (45,54).…”

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confidence: 99%

Rex-1, a Gene Encoding a Transcription Factor Expressed in the Early Embryo, Is Regulated via Oct-3/4 and Oct-6 Binding to an Octamer Site and a Novel Protein, Rox-1, Binding to an Adjacent Site

Ben-Shushan

Thompson

Gudas

et al. 1998

Molecular and Cellular Biology

224

167

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The Rex-1 (Zfp-42) gene, which encodes an acidic zinc finger protein, is expressed at high levels in embryonic stem (ES) and F9 teratocarcinoma cells. Prior analysis identified an octamer motif in the Rex-1 promoter which is required for promoter activity in undifferentiated F9 cells and is involved in retinoic acid (RA)-associated reduction in expression. We show here that the Oct-3/4 transcription factor, but not Oct-1, can either activate or repress the Rex-1 promoter, depending on the cellular environment. Rex-1 repression is enhanced by E1A. The protein domain required for Oct-3/4 activation was mapped to amino acids 1 to 35, whereas the domain required for Oct-3/4 repression was mapped to amino acids 61 to 126, suggesting that the molecular mechanisms underlying transcriptional activation and repression differ. Like Oct-3/4, Oct-6 can also lower the expression of the Rex-1 promoter via the octamer site, and the amino-terminal portion of Oct-6 mediates this repression. In addition to the octamer motif, a novel positive regulatory element, located immediately 5 of the octamer motif, was identified in the Rex-1 promoter. Mutations in this element greatly reduce Rex-1 promoter activity in F9 cells. High levels of a binding protein(s), designated Rox-1, recognize this novel DNA element in F9 cells, and this binding activity is reduced following RA treatment. Taken together, these results indicate that the Rex-1 promoter is regulated by specific octamer family members in early embryonic cells and that a novel element also contributes to Rex-1 expression.

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Retinoic acid-mediated down-regulation of Oct3/4 coincides with the loss of promoter occupancy in vivo.

et al. 1996

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Oct3/4, a hallmark of the earliest stages of embryogenesis, is expressed in undifferentiated embryonal carcinoma (EC) and embryonic stem (ES) cells. Oct3/4 gene expression is dependent on the promoter region, the proximal enhancer and the newly identified distal enhancer. We have analysed in vivo occupancy of these elements. In undifferentiated EC and ES cells, strong footprints were detected at specific sites of all three regulatory elements. These were promptly lost upon RA treatment in ES cells and in P19 EC cells, in parallel with sharply reduced Oct3/4 mRNA levels. Thus, the occupancy of regulatory elements is coupled with Oct3/4 expression, and RA treatment causes coordinated factor displacement, leading to extinction of gene activity. In F9 EC cells, footprint was first abolished at the proximal enhancer. However, this loss of binding site occupancy did not result in a decrease in Oct3/4 mRNA levels. The partial factor displacement seen in F9 EC cells, combined with the observation that EC and ES cells utilize the proximal and distal enhancers in differential manner, indicate the complex pattern of Oct3/4 gene regulation, which could reflect a cell type‐ and lineage‐specific expression of the gene in vivo.

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A Dynamic Balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and Retinoic Acid Receptor:Retinoid X Receptor Heterodimers Regulates Oct-3/4 Expression in Embryonal Carcinoma Cells

Cited by 148 publications

References 66 publications

Functional Domains of the Human Orphan Receptor ARP-1/ COUP-TFII Involved in Active Repression and Transrepression

Functional Domains of the Human Orphan Receptor ARP-1/ COUP-TFII Involved in Active Repression and Transrepression

Rex-1, a Gene Encoding a Transcription Factor Expressed in the Early Embryo, Is Regulated via Oct-3/4 and Oct-6 Binding to an Octamer Site and a Novel Protein, Rox-1, Binding to an Adjacent Site

Retinoic acid-mediated down-regulation of Oct3/4 coincides with the loss of promoter occupancy in vivo.

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