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Query: UNIPROT:P06889 (Mol)
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The RNA polymerase II and III human small nuclear RNA promoters have a common basal element, the proximal sequence element, which binds the TATA box-binding protein-containing complex SNAPc. They also contain an enhancer characterized by a highly conserved octamer sequence, which constitutes a binding site for the broadly expressed POU domain transcription factor Oct-1. The POU domain is a bipartite DNA-binding domain consisting of a POU-homeo (POUH) domain and a POU-specific (POUs) domain joined by a flexible linker. Here, we show that the Oct-1 POU domain but not the related Pit-1 POU domain can facilitate the binding of SNAPc to the proximal sequence element, and activate transcription. The effect is probably mediated by protein-protein contacts, and 1 of 30 amino acid differences between the Oct-1 and Pit-1 POUs domains is the key determinant for the differential interaction with SNAPc and the ability to activate transcription. These results show that a function that is the hallmark of activation domains, namely, recruitment of a basal transcription complex resulting in activation of transcription, can be performed by a DNA-binding domain. In this case, subtle changes between activator DNA-binding domains, as subtle as a single amino acid difference, can profoundly affect interaction with the basal transcription machinery.
Mol Cell Biol 1996 May
PMID:The Oct-1 POU-specific domain can stimulate small nuclear RNA gene transcription by stabilizing the basal transcription complex SNAPc. 862 62

A pituitary-specific trans-acting factor, Pit-1 regulates transcriptional activity of growth hormone (GH) and prolactin (PRL) genes. Pit-1 can bind and activate the promoters of human chorionic somatomammotropin (hCS-A) and placental GH variants (hGH-V) as well. However, expression of Pit-1 in the rat placenta has not yet been elucidated. The present study aims to determine whether the Pit-1 gene is locally expressed in the rat placenta using reverse transcription-polymerase chain reaction (RT-PCR), Northern blot and Western blot hybridization, in situ hybridization and immunohistochemistry. PCR products were further analyzed by Southern hybridization and DNA sequencing. The estimated size of Pit-1 mRNA in placenta was very similar to that in anterior pituitary (AP). PCR products from placenta were exactly the same size with that from AP and confirmed as Pit-1-specific by Southern hybridization. The Pit-1 specific sequence was also confirmed by sequencing of partial amplification fragments. Immunoreactive 33 kDa Pit-1 was present in the placenta as well as in AP. Pit-1 specific mRNA and protein were localized in the trophoblast cells of placenta. These data suggest that Pit-1 is locally synthesized in the rat placenta and may be involved in the regulation of GH- and/or PRL-like gene expression in the placenta.
Mol Cell Endocrinol 1996 Apr 19
PMID:Local expression of a POU family transcription factor, Pit-1, in the rat placenta. 873 86

The five human growth hormone (GH) and chorionic somatomammotropin (CS) genes are located at a single locus on chromosome 17. These genes share extensive nucleotide sequence similarity (approximately 94%) even in their flanking DNA, yet GH-N is expressed efficiently in the pituitary under the control of the pituitary-specific factor GHF-1/Pit-1 and the remaining CS-A, CS-B, CS-L and GH-V genes are transcriptionally active in the placenta. Despite this specificity in vivo, a truncated CS-A promoter can bind GHF-1/Pit-1 and allow CS-A promoter activity in pituitary cells in vitro. With a view to assessing whether the placental genes of the GH/CS locus possess a different chromatin structure in the pituitary and are, thus, less transcriptionally active than the GH-N gene, we have compared the DNAase I sensitivity of GH/CS in isolated pituitary and placenta cell nuclei. Our data indicate that these genes are equally sensitive in isolated human pituitary nuclei. By contrast, the CS-A, CS-B and CS-L genes were significantly (P < 0.05) more sensitive than the GH-N gene in isolated human placenta nuclei. Although just not significant, the GH-V gene was slightly more sensitive than the GH-N gene. This pattern was also seen with nuclei from human choriocarcinoma BeWo and JEG-3 cells, which express low and extremely low levels of CS RNA, respectively, but was distinct from the pattern observed in the non placental human cervical carcinoma HeLa cell line. These data indicate that the inactivity of the CS genes in the pituitary does not correlate with a 'closed' chromatin structure. However, they are consistent with a role for a more 'open' chromatin conformation in placenta-specific expression, but not necessarily high levels of transcriptional activity.
Mol Cell Endocrinol 1996 Apr 19
PMID:Nuclease sensitivity of the human growth hormone-chorionic somatomammotropin locus in pituitary and placenta suggest different mechanisms for tissue-specific regulation. 873 1

We studied the effects of thyroid hormone (T3) on nuclear protein-DNA interactions by using dimethyl sulfate (DMS) and DNase I ligation-mediated PCR footprinting. We examined an endogenous gene the growth hormone (GH) gene, and a stably transfected plasmid containing the chicken lysozyme silencer (F2) T3 response element (TRE) gene, F2-TRE-TK-CAT, both in pituitary tumor (GC) cells. The 235-1 cell line, which expresses prolactin (PRL) and Pit-1, but not the T3 receptor (TR) or GH, was used as a control. DMS and DNase I footprinting identified protected G residues in the Pit-1, Sp1, and Zn-15 binding sites of the GH gene in GC, but not in 235-1, cells. There was no specific protection of the tripartite GH TRE at -180 bp against either DMS or DNase I in the absence or presence of T3 in either cell line. However, T3 increased protection of the Pit-1 and Sp1 binding sites against DMS in GC cells. In GC cells stably transfected with a plasmid containing F2-TRE-TK-CAT or TRalpha, chloramphenicol acetyltransferase expression was T3 inducible and DMS footprinting revealed both F2 TRE TR-binding half sites in a pattern suggesting the binding of TR homodimers before and during T3 exposure. We conclude that the GH gene is accessible to specific nuclear proteins in GC, but not in 235-1, cells and that T3 enhances this interaction, although there is no evidence of TR binding to the low-affinity rat GH TRE. The presence of TR binding to the high-affinity F2 TRE before and during T3 exposure suggests that reversible interaction of T3 with DNA-bound TRs, rather than transient T3-TR contact with TREs, determines the level of T3-stimulated transcriptional activation.
Mol Cell Biol 1996 Aug
PMID:In vivo genomic footprinting of thyroid hormone-responsive genes in pituitary tumor cell lines. 875 47

Two nonallelic dwarfing mutations in mice define genes important for pituitary development and function. Mice homozygous for either the Ames (df) or Snell (Pit 1dw) dwarf mutations exhibit severe proportional dwarfism, hypothyroidism, and infertility due to the cytodifferentiation failure of three anterior pituitary cell types: thyrotropes, somatotropes, and lactotropes. Analysis of double heterozygotes and double mutants has provided evidence that the df and dw genes act sequentially in the same genetic pathway. Double heterozygotes had no reduction in growth rate or final adult size. Double homozygotes had essentially the same phenotype as the single mutants and were recovered at the predicted frequency, indicating that there are no previously unrecognized, redundant functions of the two genes. Several lines of evidence demonstrate that df acts earlier in the differentiation pathway than Pit1. The df mutants fail to extinguish expression of the homeobox gene Rpx on embryonic day 13.5 (e13.5), and the size of their nascent pituitary glands is reduced by e14.5. In contrast, Pit1dw mutants down-regulate Rpx appropriately and exhibit normal cell proliferation up to e14.5. The failure to extinguish Rpx and the concomitant hypocellularity of df pituitaries suggest the importance of Rpx repression in lineage-specific cell proliferation before the appearance of lineage-specific markers. Later, Pit-1 and hypothalamic neuropeptides act sequentially to regulate marker gene transcription and cell proliferation. These results establish the time of df action in a cascade of genes that regulate pituitary ontogeny.
Mol Endocrinol 1996 Dec
PMID:The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. 896 Dec 67

The POU transcription factor Oct-4 is expressed in totipotent and pluripotent cells of the early mouse embryo and the germ cell lineage. Transactivation capacities of regions flanking the DNA binding domain of Oct-4 were analyzed in undifferentiated and differentiated cell lines. The amino- and carboxy-terminal regions (N domain and C domain) fused to the Gal4 DNA binding domain both functioned as transactivation domains in all cell lines tested. However, the C domain failed to activate transcription in some cell lines in the context of the native protein. The underlying regulatory mechanism appears to involve the POU domain of Oct-4 and can discriminate between different POU domains, since constructs in which the C domain was instead fused to the POU domain of Pit-1 were again equally active in all cell lines. These results indicate that the C domain is subject to cell-type-specific regulation mediated by the Oct-4 POU domain. Phosphopeptide analysis revealed that the cell-type-specific difference of C-domain activity correlates with a difference in Oct-4 phosphorylation status. Since Oct-4 is expressed in a variety of distinct cell types during murine embryogenesis, these results suggest an additional regulatory mechanism for determining Oct-4 function in rapidly changing cell types during development.
Mol Cell Biol 1997 Jan
PMID:The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain. 897 95

We have cloned two 1.6 kb cDNAs encoding variants of the POU-type pituitary-specific transcription factor Pit-1 from Atlantic salmon. Sequence comparison with mammalian Pit-1 revealed that the POU domain was highly similar while flanking regions were less conserved. The N-terminal region contained three insertions relative to mammalian Pit-1, one of these corresponded to the insertion found in the alternatively spliced Pit-1a isoform. While two different salmon Pit-1 transcripts were expressed, alternative splicing in the 5'-region did not appear to contribute to further transcript diversity. Both salmon Pit-1 cDNAs encoded 39.5 kDa proteins that specifically bind a consensus Pit-1 recognition sequence in vitro. The salmon Pit-1 proteins also recognized the classical octamer motif; however, a point mutation in the POU homeodomain abolished this interaction.
J Mol Endocrinol 1996 Dec
PMID:Two variants of the pituitary specific transcription factor Pit-1 in Atlantic salmon. 898 Dec 29

Pit-1 is a homeodomain transcription factor that is required for the function and survival of the hormone-secreting somatotrope, lactotrope and thyrotrope cells of the anterior pituitary gland. Within the upstream region of the mouse Pit-1 gene at around -10 kb, a complex transcriptional enhancer confers autoregulation and response to hormones and morphogens upon the gene. We demonstrate that this enhancer is conserved in both sequence and function and that related sequences are present in other rodents. Enhancer sequences from mouse, rat and hamster Pit-1 genes activated transcription from Pit-1 promoter reporter genes in a pituitary progenitor cell line, in somatolactotrope cells and conferred pituitary cell-specific activation on heterologous promoters. Elements allowing regulation by vitamin D3, pituitary-specific factors and Pit-1-dependent response to retinoic acid are well conserved. Studies comparing distal enhancer activity with that of a second proposed enhancer sequence at -3 to -5 kb in the rat Pit-1 gene revealed that the distal enhancer has markedly higher activity than the -3 to -5 kb region in both progenitor and differentiated pituitary cell lines. The functional conservation of the distal enhancer element suggests that it is crucial to the maintenance and cell-specific regulation of the Pit-1 gene.
Mol Cell Endocrinol 1996 Nov 29
PMID:Function of the conserved Pit-1 gene distal enhancer in progenitor and differentiated pituitary cells. 902 35

The pituitary-specific, POU-homeodomain factor GHF-1/Pit-1 is necessary, but not sufficient, for cell-specific expression of prolactin (PRL), growth hormone (GH), and thyrotropin. Combinatorial interactions of GHF-1 with other factors are likely to be required; however, such factors and their mechanisms of action remain to be elucidated. Here we identify Ets-1 as a factor that functionally and physically interacts with GHF-1 to fully reconstitute proximal PRL promoter activity. In contrast, Ets-2 has no effect, and the alternatively spliced GHF-2/Pit-1beta variant fails to synergize with Ets-1. The Ets-1-GHF-1 synergy requires a composite Ets-1-GHF-1 cis element and is dependent on an Ets-1-specific protein domain. Furthermore, the ancestrally related and GHF-1-dependent GH promoter, which lacks this composite element, does not exhibit this response. Finally, Ets-1, but not Ets-2, binds directly to GHF-1 and GHF-2. These data show that a functional interaction of GHF-1 and Ets-1, acting via a composite DNA element, is required to establish lactotroph-specific PRL gene expression, thus providing a molecular mechanism by which GHF-1 can discriminate between the GH and PRL genes. These results underscore the importance of transcription factors that are distinct from, but interact with, homeobox proteins to establish lineage-specific gene expression.
Mol Cell Biol 1997 Mar
PMID:Interaction of Ets-1 and the POU-homeodomain protein GHF-1/Pit-1 reconstitutes pituitary-specific gene expression. 903 33

Studies by Agellon et al. (Mol. Reprod. Dev. 1, 11-17) showed the presence of two growth hormone (rtGH1 and rtGH2) mRNA species in pituitary glands of adult rainbow trout (Oncorhynchus mykiss). In this study, we have detected rtGH1 and rtGH2 mRNAs in pituitary glands of rainbow trout from fry to 2 years of age. The level of rtGH1 mRNA is notably higher than that of rtGH2 mRNA in 10-day-old fry and 2-year-old females. These results suggest differential expression of rtGH1 and rtGH2 genes in different sexes and developmental stages. As a step toward elucidating the mechanism of differential expression of both GH genes, DNA fragments encoding rtGH1 gene and the promoter/regulatory region of rtGH2 gene were isolated and characterized. Rainbow trout GH genes span approximately 4.5 kb and are composed of six exons and five introns. The 5'-flanking region of both genes contain consensus sequences for TATA boxes and several Pit-1 binding sequences. Consensus sequences related to the cAMP response element, thyroid hormone response element, retinoic acid response element, estrogen response element (ERE), and glucocorticoid response element are present not only in the 5'-flanking region, but also in introns and exons in rtGH1 gene. These hormone response elements, except ERE, are also present in rtGH2 gene.
 ...
PMID:Characterization of rainbow trout (Oncorhynchus mykiss) growth hormone 1 gene and the promoter region of growth hormone 2 gene. 914 42


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