Disease relevance of Nr2f1

• P19 embryonal carcinoma cells have been used as a model system to study COUP-TF regulation [1].
• Dual transcriptional control by Ear3/COUP: negative regulation through the DR1 direct repeat and positive regulation through a sequence downstream of the transcriptional start site of the mouse mammary tumor virus promoter [2].
• In adenovirus type 12 (Ad12) transformed cells, a high level of binding activity of COUP-TF to the major histocompatibility complex (MHC) class I enhancer correlates with the down-regulation of class I transcription, which, in turn, contributes to tumorigenesis [3].
• To study the possible function of COUP-TF I during neuronal differentiation, we generated COUP-TF I overexpressing teratocarcinoma PCC7 cell lines and analyzed retinoic acid (RA)-induced neuronal differentiation of these cells [4].

High impact information on Nr2f1

• Our results substantiate that COUP-TFI, an intrinsic factor, may work in concert with Pax6 and Emx2 to specify neocortical identity [5].
• The spatial and temporal expression pattern of COUP-TFI suggested a role in specification of the neocortex and in maintaining cortical identity [5].
• Altered region-specific expression of marker genes in the cortex as well as miswired area-specific connections between the cortex and the thalamus in COUP-TFI null mice indicate COUP-TFI plays a critical role in regulating early regionalization [5].
• Multiple COUP-TF members have been cloned and they share a high degree of sequence homology between species as divergent as Drosophila and humans, suggesting a conservation of function through evolution [6].
• COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action [7].

Biological context of Nr2f1

• We showed that COUP-TFI is expressed in the stroma and mesenchymal cells at embryonic d 11.5 (E11.5) and expression persists throughout embryonic development [8].
• The COUP-TF nuclear receptors regulate cell migration in the mammalian basal forebrain [9].
• 5. In the present study, we present evidence suggesting that chicken ovalbumin upstream promoter-transcription factor (COUP-TF) members antagonize RA-induced Cdx1 expression by competing with retinoid X receptor-retinoic acid receptor heterodimers for binding to the Cdx1 RA response element [10].
• Down-regulation of the MHC class I enhancer in tumorigenic Ad12 cells is associated with strong binding of COUP-TF and negligible binding of activator NF-kappaB [11].
• In transient transfections of a reporter driven by the MRE-PPRE in a heterologous or in the homologous promoter context, COUP-TF strongly antagonizes the transactivation by PPAR alpha RXR alpha in the absence of exogenously added ligands [12].

Anatomical context of Nr2f1

• In the adult kidney, only mesangial cells show meaningful COUP-TFI expression [8].
• However, COUP-TF1 and ARP-1 were found to be expressed predominantly in the developing central nervous system in mutually exclusive domains [13].
• High expression of COUP-TF I was detected in the olfactory nucleus, in neocortex layers I/II and V/VL, in the dentate gyrus and in areas CA1/CA3/CA4 of the hippocampus, and in the granular layer of the cerebellum [14].
• Only low amounts of COUP-TF I mRNA were detected in the ventral, the laterodorsal and in the interanteromedial thalamic nuclei [14].
• Small amounts of COUP-TF I transcripts were also found in the epithelial layer of the ventricle and in arachnoid membranes [14].

Associations of Nr2f1 with chemical compounds

• We conclude that the antagonism by COUP-TF uncovers differential activation states of PPAR alpha/RXR alpha heterodimers in the absence and in the presence of 9-cis RA [12].
• Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) genes encode transcription factors belonging to the orphan subfamily of the steroid/thyroid hormone receptor superfamily [15].
• Likewise, overexpression of the COUP-TF expression vector blocked the estrogen-stimulated response of mERM in transfected cells [16].
• In mammals, the COUP-TF-family consisting of two structurally related proteins, COUP-TFI and COUP-TFII belongs to the orphan member of the steroid/thyroid hormone receptor superfamily [17].
• Following 2 days of RA treatment, increased binding of COUP-TF to the ARE7 oligomer also occurs [18].

Physical interactions of Nr2f1

• By comparison, in nontumorigenic Ad5 cells, class I expression is high due to negligible binding of COUP-TF and strong binding of NF-kappaB [11].
• Inhibitors of preadipocyte differentiation induce COUP-TF binding to a PPAR/RXR binding sequence [18].

Regulatory relationships of Nr2f1

• Together with other data, these findings suggest a model by which COUP-TF expression is induced by RA in the trunk region as a negative feedback mechanism to restrict Cdx1 expression to the caudal embryo [10].
• Although 9-cis RA did not further enhance the transcriptional effects of the heterodimers activated by ciprofibrate, it greatly impaired the suppressive effects of COUP-TF on the ciprofibrate activated PPAR alpha/RXR alpha [12].
• Finally, immunohistochemical studies reveal that COUP-TF is specifically expressed in the immature fetal and early neonatal Purkinje cell and that this expression diminishes coincident with thyroid hormone induction of PCP-2 expression [19].
• Additionally, COUP-TF I enhanced retinoic acid response element-dependent reporter gene expression in 3T3 fibroblasts, indicating that COUP-TF I can modulate transcriptional activation in these cells [20].

Other interactions of Nr2f1

• The DNA binding activities and nuclear expression of Sp1/3 and COUP-TF in normal fetal mouse heart were similar to those in the hypertrophied adult heart [21].
• Here, we show that in the MZ, the nuclear receptor COUP-TFI is localized in calbindin-positive cells and not in reelin-positive cells [22].
• Using this approach, we isolated clones encoding the orphan nuclear receptors chicken ovalbumin upstream promoter-transcription factor (COUP-TF) 2 and COUP-TF3 [23].
• Taken together, these findings suggest that FOG-2 functions as a corepressor for both GATA and COUP-TF proteins [23].
• The molecular mechanism of this repression is due to the competition between COUP-TF and the estrogen receptor for binding at identical contact sites in the overlapping region of the mERM [16].

Analytical, diagnostic and therapeutic context of Nr2f1

• As a prototype for our analysis, we investigated the expression patterns of chicken ovalbumin upstream promoter transcription factor (COUP-TF) -I and -II in more details during embryonic development and in the adult by immunohistochemistry [8].
• Next, with the help of transplantations and gain-of-function studies in organotypic cultures, we have shown that COUP-TFI and COUP-TFII are expressed in distinct and non-overlapping migratory routes [9].
• COUP-TF I mRNA levels were reduced in the spinal cord ventricular zone (VZ) after treatment, whereas in the telencephalon, mRNA levels were unaffected in the VZ and increased in the intermediate zone (IZ) [24].
• In contrast, high COUP-TFI expression impeded the neuronal differentiation of P19 cells induced with RA, resulting in cell cultures lacking neurons [25].

References