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Results for “POU Domain Factors”

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PubMed2002

Characterization of transactivation domain and developmental expression of pituitary specific transcription factor, Pit-1 of ayu (Plecoglossus altivelis).

Pit-1 is a pituitary-specific transcription factor, which regulates the expression of growth hormone, prolactin, and thyroid stimulating hormone-beta genes. We previously reported the expression of a Pit-1 gene from ayu (Plecoglossus altivelis), which is an important cultivated food fish in Taiwan and Japan. Comparison of ayu Pit-1 with that of salmon, turkey, and rodent, revealed that the Pit-1 structure is highly conserved through vertebrates, especially in POU-specific and POU-homeo domains. The variation among fish, bird, and mammal are mainly found in transactivation domain by alternative splicing and initiation. Three insertions were found. The gamma-insert in fish Pit-1 is homologous to the exon 2a of avian Pit-1, which is not found in mammals. The beta-insert of fish Pit-1 is homologous to the 28 amino acids (a.a.) and 26 a.a. insert of avian Pit-1 beta(*) and mammalian Pit-1 beta, respectively. An additional similarity was noticed between fish and bird, as both of them contain 7 a.a. insert that is not present in mammalian Pit-1. By site directed mutagenesis, we demonstrated that the beta, gamma, and the 7 a.a. inserts of ayu Pit-1 are critical for activation of zebrafish growth hormone promoter. The ayu Pit-1 protein was found to be expressed specifically in pituitary gland, and its mRNA was first detected at embryonic day 4, significantly increased at embryonic day 5, then sustained to time of hatching at day 8.

3T3 Cells↗

PubMed2006

Klf4 cooperates with Oct3/4 and Sox2 to activate the Lefty1 core promoter in embryonic stem cells.

Although the POU transcription factor Oct3/4 is pivotal in maintaining self renewal of embryonic stem (ES) cells, little is known of its molecular mechanisms. We previously reported that the N-terminal transactivation domain of Oct3/4 is required for activation of Lefty1 expression (H. Niwa, S. Masui, I. Chambers, A. G. Smith, and J. Miyazaki, Mol. Cell. Biol. 22:1526-1536, 2002). Here we test whether Lefty1 is a direct target of Oct3/4. We identified an ES cell-specific enhancer upstream of the Lefty1 promoter that contains binding sites for Oct3/4 and Sox2. Unlike other known Oct3/4-Sox2-dependent enhancers, however, this enhancer element could not be activated by Oct3/4 and Sox2 in differentiated cells. By functional screening of ES-specific transcription factors, we found that Krüppel-like factor 4 (Klf4) cooperates with Oct3/4 and Sox2 to activate Lefty1 expression, and that Klf4 acts as a mediating factor that specifically binds to the proximal element of the Lefty1 promoter. DNA microarray analysis revealed that a subset of putative Oct3/4 target genes may be regulated in the same manner. Our findings shed light on a novel function of Oct3/4 in ES cells.

Animals↗

PubMed1997

Molecular cloning of gilthead seabream (Sparus aurata) pituitary transcription factor GHF-1/Pit-1.

We report here the complete nucleotide sequence of a cDNA clone encoding Sparus aurata GHF-1/Pit-1 isolated from an expression library prepared from gilthead seabream pituitary gland poly(A)+ RNA. The cDNA sequence (saGHF-1/Pit-1) encodes a protein of 371 amino acids (aa) containing a POU domain (aa 194-343) and a transactivation, STA domain (aa 1-128). Northern blot hybridization of pituitary RNA detected a single 3.0 kb band and a rat GHF-1/Pit-1 antiserum was found to immunoreact with pituitary protein species of 42 kDa by Western blot analysis. When compared with mammalian GHF-1/Pit-1 aa sequence, the POU and STA domains of saGHF-1/Pit-1 protein show 83% and 48% aa identity, respectively. In spite of the low homology of the transactivation domain, saGHF-1/Pit-1 is able to activate the transcription of the human growth hormone promoter.

Amino Acid Sequence↗

PubMed2004

Distinct domains of Brn-3a regulate apoptosis and neurite outgrowth in vivo.

The Brn-3a transcription factor is critical for the normal development of the nervous system, promoting both neuronal survival and neurite outgrowth. By manipulating the Brn-3a gene in intact mice, we show that these two functions are separately controlled with an N-terminal domain being essential for neuronal survival, whereas the POU domain is essential for neurite outgrowth. Hence the two naturally occurring forms of Brn-3a, which either contain or lack the N-terminal domain, are likely to play distinct roles in the nervous system.

Animals↗

PubMed2006

The human OCT-4 isoforms differ in their ability to confer self-renewal.

OCT-4 transcription factors play an important role in maintaining the pluripotent state of embryonic stem cells and may prevent expression of genes activated during differentiation. Human OCT-4 isoform mRNAs encode proteins that have identical POU DNA binding domains and C-terminal domains but differ in their N-terminal domains. We report here the cloning and characterization of the human OCT-4B isoform. Human OCT-4B cDNA encodes a 265-amino acid protein with a predicted molecular mass of 30 kDa. Embryonic stem (ES) cell-based complementation assays using ZHBTc4 ES cells showed that unlike human OCT-4A, OCT-4B cannot sustain ES cell self-renewal. In addition, OCT-4B does not bind to a probe carrying the OCT-4 consensus binding sequence, and we demonstrate that two separate regions of its N-terminal domain are responsible for inhibiting DNA binding. We also demonstrate that OCT-4B is mainly localized to the cytoplasm. Overexpression of OCT-4B did not activate transcription from OCT-4-dependent promoters, although OCT-4A did as reported previously. Furthermore, transcriptional activation by human OCT-4A was not inhibited by co-expression of OCT-4B. Taken together, these data suggest that the DNA binding, transactivation, and abilities to confer self-renewal of the human OCT-4 isoforms differ.

Animals↗

PubMed2005

Identification of the 'NORE' (N-Oct-3 responsive element), a novel structural motif and composite element.

N-Oct-3 is a neuronal transcription factor widely expressed in the developing mammalian central nervous system, and necessary to maintain neural cell differentiation. The key role of N-Oct-3 in the transcriptional regulation of a multiplicity of genes is primarily due to the structural plasticity of its so-called 'POU' (acronym of Pit, Oct, Unc) DNA-binding domain. We have recently reported about the unusual dual neuro-specific transcriptional regulation displayed by N-Oct-3 [Blaud,M., Vossen,C., Joseph,G., Alazard,R., Erard,M. and Nieto,L. (2004) J. Mol. Biol., 339, 1049-1058]. To elucidate the underlying molecular mechanisms, we have now made use of molecular modeling, DNA footprinting and electrophoretic mobility shift assay techniques. This combined approach has allowed us to uncover a novel mode of homodimerization adopted by the N-Oct-3 POU domain bound to the neuronal aromatic amino acids de-carboxylase and corticotropin-releasing hormone gene promoters and to demonstrate that this pattern is induced by a structural motif that we have termed 'NORE' (N-Oct-3 responsive element), comprising the 14 bp sequence element TNNRTAAATAATRN. In addition, we have been able to explain how the same structural motif can also induce the formation of a heterodimer in association with hepatocyte nuclear factor 3beta(/Forkhead box a2). Finally, we discuss the possible role of the NORE motif in relation to neuroendocrine lung tumor formation, and in particular the development of small cell lung cancer.

Amino Acid Motifs↗

PubMed1991

The oct3 gene, a gene for an embryonic transcription factor, is controlled by a retinoic acid repressible enhancer.

Oct3 is an embryonic octamer-binding transcription factor, whose expression is rapidly repressed by retinoic acid (RA). In this report, we have determined the transcriptional control region of the oct3 gene and studied the mechanism of the RA-mediated repression. The chromosomal oct3 gene consists of five exons. Three subdomains of the POU region and transactivating domain are located in separate exons. Transcription initiates at multiple sites in the GC-rich region lacking a typical TATA box. The upstream 2 kb region can confer the cell type-specific expression and RA-mediated repression. Analysis of the upstream region by deletion mutagenesis locates a cis element (RARE1) which functions as a stem cell-specific, yet RA-repressible, enhancer. Footprint and gel-retardation assays show that RARE1 is composed of two domains, each of which is recognized by distinct factors. Microinjection of oct3-lacZ constructs into fertilized eggs indicates that RARE1 can function in early embryos. We suggest that RARE1 is a critical cis element for oct3 gene expression in embryonic stem cells and for the RA-mediated repression.

Amino Acid Sequence↗

PubMed1992

Segments of the POU domain influence one another's DNA-binding specificity.

The ubiquitously expressed mammalian POU-domain protein Oct-1 specifically recognizes two classes of cis-acting regulatory elements that bear little sequence similarity, the octamer motif ATGCAAAT and the TAATGARAT motif. The related pituitary-specific POU protein Pit-1 also recognizes these two motifs but, unlike Oct-1, binds preferentially to the TAATGARAT motif. Yet in our assay, Pit-1 still binds octamer elements better than does the octamer motif-binding protein Oct-3. The POU domain is responsible for recognizing these diverse regulatory sequences through multiple DNA contacts that include the two POU subdomains, the POU-specific region, and the POU homeodomain. The DNA-binding properties of 10 chimeric POU domains, in which different POU-domain segments are derived from either Oct-1 or Pit-1, reveal a high degree of structural plasticity; these hybrid proteins all bind DNA well and frequently bind particular sites better than does either of the parental POU domains. In these chimeric POU domains, the POU-specific A and B boxes and the hypervariable POU linker can influence DNA-binding specificity. The surprising result is that the influence a particular segment has on DNA-binding specificity can be greatly affected by the origin of other segments of the POU domain and the sequence of the binding site. Thus, the broad but selective DNA-binding specificity of Oct-1 is conferred both by multiple DNA contacts and by dynamic interactions within the DNA-bound POU domain.

Amino Acid Sequence↗

PubMed1995

Nubbin encodes a POU-domain protein required for proximal-distal patterning in the Drosophila wing.

The nubbin gene is required for normal growth and patterning of the wing in Drosophila. We report here that nubbin encodes a member of the POU family of transcription factors. Regulatory mutants which selectively remove nubbin expression from wing imaginal discs lead to loss of wing structures. Although nubbin is expressed throughout the wing primordium, analysis of genetic mosaics suggests a localized requirement for nubbin activity in the wing hinge. These observations suggest the existence of a novel proximal-distal growth control center in the wing hinge, which is required in addition to the well characterized anterior-posterior and dorsal-ventral compartment boundary organizing centers.

Animals↗

PubMed1990

Binding of a Drosophila POU-domain protein to a sequence element regulating gene expression in specific dopaminergic neurons.

Several genes have been identified that affect the specification of unique neuronal identities during development of the Drosophila central nervous system. At least two of these genes, fushi tarazu (ftz) and even-skipped (eve) share a common structural motif, the homoeobox, which encodes a sequence-specific DNA-binding domain (homoeodomain). A family of related proteins has been recently characterized in mammals and nematodes that contain a diverged homoedomain as part of a structure referred to as a POU domain. Mammalian genes encoding POU domains have region-specific patterns of expression in the central nervous system, indicating a potential role for them in the regulation of neuronal development. The nematode POU-domain gene, unc-86, is involved in the determination of neuroblast lineages leading to serotonergic and dopaminergic neurons. We have now identified a Drosophila gene, Cfla, encoding a sequence-specific DNA-binding protein containing a highly conserved POU domain. The Cfla gene product binds to a DNA element required for expression of the dopa decarboxylase gene (Ddc) in selected dopaminergic neurons, implying that it functions as a neuron-specific transcription factor.

Amino Acid Sequence↗

PubMed1995

Salmon HNF1: cDNA sequence, evolution, tissue specificity and binding to the salmon serum albumin promoter.

cDNA clones coding for the transcription factor HNF1 have been isolated from Atlantic salmon (Salmo salar L.). The 559 amino acid residue long encoded protein shows high conservation, with respect to other species, of the domains necessary for DNA-binding: the HNF1 atypical homeodomain, the POU related sequence and the dimerisation domain. Alignment with rat HNF1 protein reveals that the transcription activation domains ADI and ADIII are relatively conserved in the fish sequence whereas ADII is not. Phylogenetic analysis indicates that higher vertebrate HNF1s and the related variant HNF1s (vHNF1s) are more closely related to each other than any of them is to Salmon HNF1, suggesting that the duplication event from which HNF1 and vHNF1 genes arose occurred after the divergence of the tetrapod and teleost ancestors. Northern blot analysis show a single transcript, of about 2.6 kb, which is not exclusive to liver but is also present in intestine, kidney and spleen. Using polymerase chain reaction (PCR) we have isolated the salmon albumin gene promoter which contains, upstream of the TATA box, a potential binding site for HNF1. The salmon HNF1 protein synthesized by in vitro transcription-translation of the full-length cDNA is able to bind specifically with equivalent affinities to either the rat or salmon albumin promoter.

Amino Acid Sequence↗

PubMed1999

Functional interaction between Oct-1 and retinoid X receptor.

The retinoid X receptor (RXR) is a member of the nuclear hormone receptor superfamily and heterodimerizes with a variety of other family members such as the thyroid hormone receptor (TR),1 retinoic acid receptor, vitamin D receptor, and peroxisome proliferator-activated receptor. Therefore, RXR is supposed to play a key role in a ligand-dependent regulation of gene transcription by nuclear receptors. In this study, we have identified the octamer-binding transcription factor-1 (Oct-1) as a novel interaction factor of RXR. In vitro pull-down assays using RXR deletion mutants showed that the interaction surfaces were located in the region encompassing the DNA binding domain (C domain) and the hinge domain (D domain) of RXR. We also showed that RXR interacted with the POU homeodomain but not with the POU-specific domain of Oct-1. Gel shift analysis revealed that Oct-1 reduced the binding of TR/RXR heterodimers to the thyroid hormone response element (TRE). In transient transfection assays using COS1 cells, Oct-1 repressed the T3-dependent transcriptional activity of TR/RXR heterodimers, consistent with in vitro DNA binding data; however, transcriptional activation by Gal4-TR(LBD) (LBD, ligand binding domain), which lacks its own DNA binding domain but retains responsiveness to T3, was not influenced by Oct-1. These results suggest that Oct-1 functionally interacts with RXR and negatively regulates the nuclear receptor signaling pathway by altering the DNA binding ability of the receptors.

Animals↗

PubMed1991

The herpes simplex virus trans-activator VP16 recognizes the Oct-1 homeo domain: evidence for a homeo domain recognition subdomain.

The homeo domain of the Oct-1 transcription factor directs formation of a multiprotein-DNA complex containing Oct-1, the herpes simplex virus (HSV) trans-activator VP16, and a second host cell factor (HCF). This VP16-induced complex alters the regulatory activity of Oct-1, in part, by associating it with the potent VP16 acidic transcriptional activation domain. Here, we show that in the absence of HCF, VP16 can recognize specifically the Oct-1 homeo domain. A region of VP16 near the acidic activation domain appears to be involved exclusively in homeo domain recognition because a 4-amino-acid insertion within this region only affects the ability of VP16 to interact with Oct-1, leaving its DNA- and HCF-binding activities unchanged. A 33-amino-acid peptide containing this region complexes with the Oct-1 POU domain bound to DNA, suggesting that this VP16 region contains an autonomous homeo domain recognition subdomain.

Amino Acid Sequence↗

PubMed2004

Two distinct teleost hepatocyte nuclear factor 1 genes, hnf1alpha/tcf1 and hnf1beta/tcf2, abundantly expressed in liver, pancreas, gut and kidney of zebrafish.

Two distinct forms of zebrafish hepatocyte nuclear factor 1 (hnf1) were identified and referred to as hnf1alpha/tcf1 and hnf1beta/tcf2. Both hnf1 genes were shown to be expressed abundantly in liver, pancreas, gut and kidney. Zebrafish HNF1alpha and HNF1beta proteins contain all HNF1 signature domains including the dimerization domain, POU-like domain and atypical homeodomain. Sequence and phylogenetic analysis reveals that zebrafish hnf1alpha is closer to tetrapodian hnf1alpha than to tetrapodian hnf1beta and zebrafish hnf1beta is highly conserved with tetrapodian hnf1beta. Existences of hnf1alpha and hnf1beta in teleost zebrafish, tilapia and fugu suggest that hnf1 gene duplication might occur before the divergence of teleost and tetrapod ancestors. Zebrafish hnf1alpha and hnf1beta genes were mapped to linkage group LG8 and LG15 in T51 panel by RH mapping and are composed of 10 and 9 exons, respectively. Zebrafish hnf1beta gene with at least 11 genes in LG15 was identified to maintain the conserved synteny with those of human in chromosome 17 and those of mouse in chromosome 11. Our results indicate that distinct hnf1alpha and hnf1beta genes in teleosts had been evolved from the hnf1 ancestor gene of chordate.

Amino Acid Sequence↗

PubMed1990

Transcription factor Oct-2A contains functionally redundant activating domains and works selectively from a promoter but not from a remote enhancer position in non-lymphoid (HeLa) cells.

In non-lymphoid cells such as HeLa cells, ectopic expression of the lymphocyte-specific transcription factor Oct-2A can activate reporter genes whose promoters consist of a single octamer sequence (ATTTGCAT) upstream of a TATA box. While the factor is strongly active in a promoter position, it tails as an enhancer factor: an enhancer consisting of multiple copies of the octamer sequence placed downstream of the reporter gene is not active in HeLa cells, even at high concentration of Oct-2A. In B lymphoid cells, however, the same enhancer is highly active. This could mean that an additional factor is required for enhancer activation in B cells. Furthermore, we have tested the transcriptional activation potential of Oct-2A with a series of N-terminal and C-terminal deletions. We show that a glutamine-rich domain near the N-terminus is required for full activity. Otherwise, large segments of the N-terminal half or the entire C-terminal region are dispensable in our assay, as long as the deletions do not impinge on the conserved POU domain which is sufficient for DNA binding. While N-terminal and C-terminal regions can functionally compensate for each other, a combined deletion that only retains the POU domain is a strong down mutation. We also find that activity depends on the promoter structure of the reporter gene: the POU domain by itself shows some activity with a promoter where the octamer sequence is located very close to the TATA box, but no activity with another promoter construction where the octamer sequence is located further upstream. The two promoters also respond differently to the deletion of the glutamine-rich stretch important for transcriptional activation. From these experiments we consider it likely that the natural octamer factor variants can selectively activate the different naturally occurring octamer-containing promoters.

Amino Acid Sequence↗

PubMed2006

PSPC1, NONO, and SFPQ are expressed in mouse Sertoli cells and may function as coregulators of androgen receptor-mediated transcription.

In Sertoli cells of testis, androgen receptor-regulated gene transcription plays an indispensable role in maintaining spermatogenesis. Androgen receptor activity is modulated by a number of coregulators which are associated with the androgen receptor. Non-POU-domain-containing, octamer binding protein (NONO), a member of the DBHS-containing proteins, complexes with androgen receptor and functions as a coactivator for the receptor. Paraspeckle protein 1 alpha isoform (PSPC1, previously known as PSP1) and Splicing factor, proline- and glutamine-rich (SFPQ, previously known as PSF), other members of the DBHS-containing proteins, are also found in androgen receptor complexes, suggesting that these DBHS-containing proteins may cooperatively regulate androgen receptor-mediated gene transcription. We demonstrated that PSPC1, NONO, and SFPQ are coexpressed in Sertoli cell line TTE3 and interact reciprocally. The effect of the DBHS-containing proteins on the transcriptional activity was assessed using the construct containing androgen-responsive elements followed by a luciferase gene. The results showed that all the DBHS-containing proteins activate androgen receptor-mediated transcription, and PSPC1 is the most effective coactivator among them. Furthermore, we confirmed the presence of PSPC1, NONO, and SFPQ proteins in Sertoli cells of adult mouse testis sections. These observations suggest that PSPC1, NONO, and SFPQ form complexes with each other in Sertoli cells and may regulate androgen receptor-mediated transcriptional activity.

Animals↗

PubMed1990

A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells.

We have identified a novel octamer binding factor (Oct-3) in P19 embryonal carcinoma cells. Oct-3, which recognizes the typical octamer motif (ATTTGCAT) as well as the AT-rich sequence TTAAAATTCA, is present in P19 stem cells but disappears when the cells are induced to differentiate by retinoic acid (RA). Cloned cDNA corresponding to Oct-3 encodes a protein of 377 amino acids. Oct-3 has a conserved POU domain, but the remaining part is distinct from other POU domain-containing proteins such as Oct-1 and Oct-2. mRNA of 1.5 kb coding for Oct-3 is abundant in P19 stem cells but is dramatically repressed during RA-induced differentiation. Repression of the 1.5 kb mRNA is rapid and specific to RA. In mouse, oct-3 mRNA is undetectable in all the adult organs examined. The N-terminal proline-rich region of Oct-3, when fused to the DNA binding domain of c-Jun, functions as a transcriptional activating domain. We suggest that Oct-3 is a novel octamer binding transcription factor that is developmentally regulated during mouse embryogenesis.

Amino Acid Sequence↗

PubMed1995

Functional domains in the oxytocin gene for regulation of expression and biosynthesis of gene products.

In the oxytocin (OT) gene several regions can be discerned that have a function in regulating its expression. Firstly, in the proximal 5' flanking region regulatory elements have been discovered that are targets for transcription factors of the nuclear hormone receptor family. Through these elements the OT gene of rat and man is responsive to estrogens, thyroid hormones and retinoids. Furthermore, these elements can be employed by the nuclear hormone orphan receptor family for repressive or inductive actions. In the distal 5' flanking region the POU class III proteins Brn-1, Brn-2, Brn-4, that are expressed in magnocellular neurons, and Oct-6 are able to bind, but do not display a significant regulatory activity on the OT gene in heterologous expression systems. Secondly, the OT precursor harbours both the biologically active hormone and the protein neurophysin that is able to associate with the hormone. Heterologous expression of wild-type and mutant vasopressin cDNAs in peptidergic cell lines shows that the highly homologous vasopressin-associated neurophysin domain associates with the hormone domain within the prohormone. This intramolecular interaction between two prohormone domains serves an essential intracellular function, i.e. the proper sorting of the prohormone into the regulated secretory pathway.

Animals↗