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At least 19 recordsLinked to original sources
PubMed1991

Octamania: the POU factors in murine development.

Much effort has been directed towards the investigation of regulatory processes in the early mouse embryo. Several multigene families of developmental control genes have been identified. The POU family is a group of related transcription factors containing a particular type of bipartite DNA-binding domain. Members of this family show distinct expression patterns during embryonic development. Two members, Oct-4 and Oct-6, are expressed as early as in the preimplantation embryo and thus may regulate early events of murine development.

Amino Acid Sequence↗
PubMed1990

Oct-4: a germline-specific transcription factor mapping to the mouse t-complex.

Oct-4 is a maternally expressed octamer-binding protein encoded by the murine Oct-4 gene. It is present in unfertilized oocytes, but also in the inner cell mass and in primordial germ cells. Here we show that the ectopic expression of Oct-4 in HeLa cells is sufficient for transcriptional activation from the octamer motif, indicating that Oct-4 is a transcription factor. Therefore, Oct-4 is the first transcription factor described that is specific for the early stages of mouse development. The spatial and temporal expression patterns were further determined using in situ hybridization. With this technique Oct-4 expression is detected in the oocyte, in the blastocyst and before gastrulation in the embryonic ectoderm. After day 8 Oct-4 expression decreases and is restricted to primordial germ cells from about day 8.5 onwards. Therefore Oct-4 is a transcription factor that is specifically expressed in cells participating in the generation of the germline lineage. Linkage analysis using B X D recombinant inbred mouse strains demonstrates that Oct-4 maps to chromosome 17 in or near the major histocompatibility complex. Several mouse mutants in the distal region of the mouse t-complex affecting blastocyst and embryonic ectoderm formation also map to this region.

Animals↗
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↗
PubMed1993

Hybrid cell extinction and re-expression of Oct-3 function correlates with differentiation potential.

The Oct-3 gene is expressed in highly undifferentiated cells and is implicated in mammalian early embryogenesis. We have generated a series of hybrid cells between pluripotent embryonal carcinoma cells (Oct-3+) and fibroblasts (Oct-3-), and have studied the regulation and function of Oct-3. Upon fusion, the hybrid cells differentiated to nestin+/Brn-2+ cells resembling neuroepithelial stem cells. Expression of Oct-3 was extinguished at the transcriptional level in all the hybrid cells examined. The Oct-3 modulating activity required for the Oct-3-mediated enhancer activation was also extinguished. When the Oct-3 transactivating function was introduced into the hybrid cells, they transformed into morphologically distinct nestin-/Brn-2- cells ('revertants'). When the 'revertant' cells subsequently lost Oct-3 expression, they differentiated back to nestin+/Brn-2+ cells. The close correlation between the phenotypic changes and the gain/loss of Oct-3 function indicates that Oct-3 can induce dedifferentiation of the neural cells.

Animals↗
PubMed1995

Structure of the Oct-3 POU-homeodomain in solution, as determined by triple resonance heteronuclear multidimensional NMR spectroscopy.

The POU-homeodomain (POUH) forms the bipartite DNA-binding POU domain in association with the POU-specific domain. The 1H, 15N, and 13C magnetic resonances of the 67-amino acid long POUH of mouse Oct-3 have almost completely been assigned, mainly through the combined use of three-dimensional triple resonance NMR methods. Based on the distance and dihedral angle constraints derived from the NMR data, the solution structure of the POUH domain has been calculated by the ab initio simulated annealing method. The average RMS deviation for all backbone heavy atoms of the 20 best calculated structures for residues 9-53 of the total 67 amino acid residues is 0.44 A. The POUH domain consists of three alpha-helices (helix-I, 10-20; helix-II, 28-38; and helix-III, 42-53), and helices-II and -III form a helix-turn-helix motif. In comparison with other classical homeodomains, the folding of the three helices is quite similar. However, the length of helix-III is fairly short. In the complex of the Oct-1 POU domain with an octamer site (Klemm JD, et al., 1994, Cell 77:21-32), the corresponding region is involved in helix-III. The structural difference between these two cases will be discussed.

Amino Acid Sequence↗
PubMed1994

The octamer motif present in the Rex-1 promoter binds Oct-1 and Oct-3 expressed by EC cells and ES cells.

Rex-1 is a zinc finger-containing gene that is expressed in embryonal carcinoma (EC) cells and embryonic stem (ES) cells. Upon differentiation with retinoic acid (RA), transcription of the Rex-1 gene decreases rapidly. Analysis of the 5'-flanking region of the Rex-1 gene identified a consensus motif for the octamer family of transcription factors that stimulates expression from the Rex-1 promoter. In this report, we utilized gel mobility shift analysis to examine the binding of transcription factors to the Rex-1 octamer motif. F9 EC cells, D3 ES cells, and human NT2/D1 EC cells each from at least two prominent DNA/protein complexes with the octamer motif. Supershift analysis identifies Oct-1 and Oct-3 in these complexes. When F9 EC cells are induced to differentiate by treatment with RA for 48 h, there is a complete loss of the DNA/protein complex containing Oct-3. In contrast, the other DNA/protein complexes, including the DNA/protein complex containing Oct-1, can still be detected. These results provide support for a role of Oct-3 in the transcription of the Rex-1 gene.

Animals↗
PubMed1995

Phosphorylation and DNA binding of the octamer binding transcription factor Oct-3.

Phosphorylation influences DNA binding and transactivator capabilities of multiple transcription factors. In this study, we demonstrate that the POU-domain transcription factor, Oct-3, can be phosphorylated in vivo. In addition, we show that in COS-1 cells Oct-3 is phosphorylated exclusively on serine residues. Lastly, we provide evidence that phosphorylation is not required for Oct-3 binding to DNA and treatment of Oct-3 with calf intestinal alkaline phosphatase does not influence its ability to bind DNA.

Alkaline Phosphatase↗
PubMed1994

Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation.

Oct-4 is the earliest expressed gene known to encode a transcription factor which is developmentally regulated during mammalian embryogenesis. In order to understand the role of Oct-4 in early murine embryogenesis, we carried out an analysis of the temporal and spatial pattern of protein expression. We report the presence of Oct-4 protein in cultured cells and murine embryos as determined by immunohistochemistry using confocal microscopy. Oct-4 protein is present in both embryonic stem cells and embryonal carcinoma cells, but is down-regulated following differentiation of these cells by culture in the absence of leukemia inhibitory factor or in the presence of retinoic acid, respectively. In embryos, the protein is found at low levels in unfertilized eggs and is localized predominantly to the pro-nuclei upon their formation following fertilization. The protein is present in the nuclei in all cleavage stages, but following differentiation of the trophectoderm at the blastocyst stage, Oct-4 protein is only expressed in the inner cell mass. The pattern of protein expression to this stage correlates well with previously reported in situ hybridization results; however, a striking difference was seen in primitive endoderm cells which had begun to differentiate and migrate along the inner surface of the trophectoderm. In direct contrast to RNA localization studies which demonstrate that there are only low levels of Oct-4 transcripts in primitive endoderm cells, protein expression in these early migrating cells is higher than in the inner cell mass.

3T3 Cells↗
PubMed1994

Localization of the OTF3 gene within the human MHC class I region by physical and meiotic mapping.

OTF3 (octamer transcription factor 3) is a transcription factor containing a POU-specific domain and a homeodomain that could play a role in early development. In situ hybridization and pairwise linkage analysis showed that OTF3 gene maps close to the human MHC (major histocompatibility complex). In this paper, we define its localization within the MHC, around 100 kb telomeric to HLA-C, using a combination of physical and genetic analyses.

Alleles↗
PubMed2025

The cGAS-STING pathway is a master regulator of OCT4 expression in persistent sarcoma cells and enhances cellular immunotherapy with NK and CIK lymphocytes.

Advanced sarcomas have a poor prognosis and limited therapeutic options. Disease recurrence is caused by persistent cells that survive drug treatments. The alkylating agent trabectedin, when combined with the poly (ADP-ribose) polymerase 1 (PARP1) inhibitor olaparib, exhibits variable antitumor effects in advanced sarcomas. In this study, we demonstrate that the expression of the transcription factor OCT4 is upregulated in persistent cells that survive treatment with trabectedin and olaparib, through the cGAS-STING-IRF3-IFNβ pathway. This route also leads to the upregulation of natural killer (NK) and cytokine-induced killer (CIK) lymphocyte activating ligands. These molecular events enhance the antitumor efficacy of immunotherapy with NK and CIK cells, targeting both the bulk population and residual drug-tolerant cells. In conclusion, the activation of the cGAS-STING pathway has a double-edged effect, enriching the OCT4+ persistent cell population while increasing the expression of NK/CIK ligands. The addition of olaparib to trabectedin potentiates the cGAS-STING pathway activation and the upregulation of NKG2DLs, while simultaneously counteracting the OCT4 overexpression. Therefore, sequential treatment with trabectedin and olaparib followed by NK/CIK immunotherapy represents a promising strategy against advanced sarcomas and warrants further investigation.

Humans↗
PubMed1993

Secondary structure of the oct-3 POU homeodomain as determined by 1H-15N NMR spectroscopy.

Most of the 1H and 15N magnetic resonances of the 66 amino acid long POU homeodomain of mouse Oct-3 have been assigned by the combined use of the two-dimensional homonuclear, and two- and three-dimensional heteronuclear NMR methods. The sequential NOE connectivities and amide proton exchange measurements indicate the presence of three helical regions within the domain. The positions of the three helices correspond well to those of other homeodomains, the three-dimensional structures of which have already been determined. The present NMR study provides the first experimental evidence for the existence of a helix-turn-helix motif in the oct-3 POU homeodomain.

Amino Acid Sequence↗
PubMed1994

Regulatory sequences required for hst-1 expression in embryonal carcinoma cells.

The hst-1 gene, which is implicated in mammalian embryonic development and morphological transformation of NIH3T3 cells, is expressed in undifferentiated F9 cells, but not in differentiated F9 and other well-differentiated cells, such as PYS-2, NIH3T3 and HeLa cells. An octamer element present in the 3' untranslated region acts as an enhancer. Although Oct3 is down-regulated when F9 cells are differentiated, transient expression of Oct3 did not enhance the hst-1 promoter activity in HeLa, NIH3T3 or PYS-2 cells. Thus, the role of Oct3 on hst-1 expression remains elusive, and an additional transcription factor which interacts may regulate hst-1 transcription in association with Oct1, Oct3 or both.

3T3 Cells↗
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↗
PubMed1991

Oct-3 is a maternal factor required for the first mouse embryonic division.

Oct-3 is a POU domain transcription factor that binds the octamer DNA motif and is present in mouse oocytes before and after fertilization. When fertilized oocytes were injected with antisense Oct-3 oligonucleotides or double-stranded DNA containing the octamer motif, embryonic DNA synthesis was inhibited and the embryos were arrested at the one-cell stage. In vitro synthesized Oct-3 mRNA rescued the developmental block induced by antisense Oct-3 oligonucleotide. We conclude that maternally inherited Oct-3 is required for DNA replication and division of the one-cell embryo.

Animals↗
PubMed1991

A nexus between Oct-4 and E1A: implications for gene regulation in embryonic stem cells.

Oct-4 is a transcription factor expressed in the pluripotent progenitor cells of the early mouse embryo. Additional factors are required for the distal activation of genes in differentiated cells containing ectopically expressed Oct-4. Here we show that Oct-4 and E1A are sufficient for distance-independent activation of the basal transcription machinery. The ratio of Oct-4 to E1A is critical for transcriptional activation, because higher levels of either factor are less efficient. Activation depends on a transactivation domain linked to the POU domain of Oct-4 and also on the conserved domain 3 of the 289RE1A protein. This domain is required for binding to the C-terminal part of Oct-4 including the POU domain. Our results indicate that E1A can serve as a bridging factor between Oct-4 and the basal initiation complex, and we postulate that an E1A-like factor acts as a cellular bridging factor of Oct-4 in pluripotent cells.

Adenovirus Early Proteins↗
PubMed1991

Chromosomal location of the octamer transcription factors, Otf-1, Otf-2, and Otf-3, defines multiple Otf-3-related sequences dispersed in the mouse genome.

Chromosomal locations have been assigned for the octamer transcription factor, Otf, gene family (previously named the octamer-binding protein, Oct, gene family) using an interspecific backcross of [(C57BL/6J x Mus spretus)F1 x C57BL/6J] mice and the BXH recombinant inbred strains. Molecular probes for Otf-1 and Otf-2 recognized single loci on mouse chromosomes 1 and 7, respectively, whereas probes for Otf-3 recognized a minimum of eight independently segregating loci (designated Otf-3a through Otf-3h). Members of the Otf-3 family mapped to mouse chromosomes 1, 2, 3, 6, 14, 17, and the X chromosome, indicating that the Otf family has become widely dispersed during evolution. Several Otf loci mapped near developmental mutations, raising the possibility that these mutations result from defects in Otf family members.

Animals↗
PubMed1991

Structure, expression and chromosomal location of the Oct-4 gene.

The map position of Oct-4 on mouse chromosome 17 is between Q and T regions in the Major Histocompatibility Complex (MHC), and it is physically located within 35 kb of a class I gene. Several Oct-4-related genes are present in the murine genome; one of them maps to chromosome 9. The genomic structure and sequence of Oct-4 determined in t-haplotypes reveals five exons, and shows no significant changes in the t12 mutant haplotype making it unlikely that Oct-4 and the t12 early embryonic lethal are the same gene. By in situ hybridization, detectable onset of zygotic Oct-4 expression does not occur until compaction begins at 8-cells, suggesting that there might be other regulatory factors responsible for initiating Oct-4 expression.

Animals↗