Activation of the glycoprotein hormone alpha-subunit promoter by a LIM-homeodomain transcription factor.

Roberson, Mark S.; Schoderbek, William E.; Tremml, Gabi; Maurer, Richard A.

doi:10.1128/mcb.14.5.2985

Cited by 144 publications

(135 citation statements)

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“…By later stages of pituitary development and in adult mammals, ␣GSU expression is limited to thyrotropes and gonadotropes (4). Gonadotrope-specific expression of the ␣GSU gene is controlled by an array of regulatory elements, including the pituitary glycoprotein hormone basal element (5,6), ␣ basal elements (6), gonadotrope-specific element (7), and tandemly repeated cAMP response elements (8 -10), as well as the intricate interplay between their cognate binding proteins (6).…”

mentioning

confidence: 99%

Embryonic Expression of the Luteinizing Hormone β Gene Appears to Be Coupled to the Transient Appearance of p8, a High Mobility Group-related Transcription Factor

Quirk

Seachrist

Nilson

2003

Journal of Biological Chemistry

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A comparison between two pituitary-derived cell lines (␣T3-1 and L␤T2) that represent gonadotropes at early and late stages of development, respectively, was performed to further elucidate the genomic repertoire required for gonadotrope specification and luteinizing hormone ␤ (LH␤) gene expression. One isolated clone that displayed higher expression levels in L␤T2 cells encodes p8, a high mobility group-like protein with mitogenic potential that is up-regulated in response to proapoptotic stimuli and in some developing tissues. To test the functional significance of this factor in developing gonadotropes, a knockdown of p8 in L␤T2 cells was generated. The loss of p8 mRNA correlated with loss of endogenous LH␤ mRNA and the loss of activity of a transfected LH␤ promoter-driven reporter, even upon treatment with gonadotropin-releasing hormone. In addition, expression of p8 mRNA in developing mouse pituitary glands mirrored its expression in the gonadotrope-derived cell lines and coincided with the first detectable appearance of LH␤ mRNA. In contrast, p8 mRNA was undetectable in the pituitary glands of normal adults. Taken together, our data indicate that p8 is a stage-specific component of the gonadotrope transcriptome that may play a functional role in the initiation of LH␤ gene expression during embryonic cellular differentiation.With its ability to stimulate gonadal steroidogenesis and gametogenesis, luteinizing hormone (LH) 1 is essential for normal reproductive function in mammals (1, 2). Luteinizing hormone is a heterodimeric protein composed of an ␣ glycoprotein hormone subunit (␣GSU) common to all members of the glycoprotein family of hormones that is non-covalently linked to a unique LH␤ subunit that confers its biological specificity (1, 2). Biosynthesis of LH depends on the coordinated expression of both the ␣GSU and LH␤ subunit genes. In humans, the single copy ␣GSU gene resides on chromosome 6q12-q21 (Locus ID 1081) while the LH␤ gene resides amid a cluster of six chorionic gonadotropin-␤ genes on chromosome 19q13.32 (Locus ID 1082). In addition to their different locations within the human genome, the pattern of expression of the genes encoding ␣GSU and LH␤ are temporally and spatially distinct.During development ␣GSU is seen throughout Rathke's pouch as early as embryonic day (e) 9.5 in the mouse (3). By later stages of pituitary development and in adult mammals, ␣GSU expression is limited to thyrotropes and gonadotropes (4). Gonadotrope-specific expression of the ␣GSU gene is controlled by an array of regulatory elements, including the pituitary glycoprotein hormone basal element (5, 6), ␣ basal elements (6), gonadotrope-specific element (7), and tandemly repeated cAMP response elements (8 -10), as well as the intricate interplay between their cognate binding proteins (6).In a fashion similar to the ␣GSU promoter, the LH␤ gene is regulated by a combinatorial array of transcription factors and regulatory elements. In this case, however, the elements consist of those that bind early growth response ...

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mentioning

confidence: 99%

Embryonic Expression of the Luteinizing Hormone β Gene Appears to Be Coupled to the Transient Appearance of p8, a High Mobility Group-related Transcription Factor

Quirk

Seachrist

Nilson

2003

Journal of Biological Chemistry

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“…5D). It is noteworthy that the latter sequence overlaps with that of Lhx2-binding site (5 0 -TACTTAGC-TAATTA-3 0 , K343/K330; Roberson et al 1994). In addition, the increased signals by Prop-1 binding appeared in the regions K476/K474 and K325/K 314 bp.…”

Section: Prop-1 Binds To A/t Rich Sequences In Agsu Promotermentioning

confidence: 92%

“…125 U AmpliTaqGold DNA polymerase (PE Applied Biosystems, Foster City, CA, USA) with 32-36 cycles of denaturation (94 8C, 30 s), annealing (55 8C, 30 s), and extension reaction (72 8C, 2 min) steps. The resulting amplified products were ligated to the secreted alkaline phosphatase (SEAP) plasmid vector, pSEAP2-Basic (Clontech Laboratories, Inc., Mountain View, CA, USA), which has no eukaryotic promoter, resulting in reporter vectors aGSU(K1059/C12), aGSU(K798/C12), aGSU(K540/C12), aGSU(K 239/C12), aGSU(K100/C12), and aGSU(K53/C12) (Roberson et al 1994); GSE/SF-1, gonadotrope-specific element/SF-1-binding site (Barnhart & Mellon 1994); GATA, GATAbinding element (Steger et al 1994); CRE, cyclic AMP-responsive element (Delegeane et al 1987); JRE, junctional response element (Andersen et al 1990); TRE, thyroid hormone responsive element (Attardi et al 1995); CArG, CArG box (Weck et al 2000); NF-Y (Keri et al 2000); EGR-1 (Tremblay & Drouin 1999); Ptx-1 (Tremblay et al 1998); SF-1 (LHb) (Brown & McNeilly 1997); TATA: TATA-box.…”

Section: Construction Of Reporter Vectors and Expression Vectormentioning

confidence: 99%

Pituitary transcription factor Prop-1 stimulates porcine pituitary glycoprotein hormone α subunit gene expression

Sato¹,

Kitahara²,

Sugiyama³

et al. 2006

Journal of Molecular Endocrinology

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Recently, we have reported that a Prophet of Pit-1 homeodomain factor, Prop-1, is a novel transcription factor for the porcine follicle-stimulating hormone b subunit (FSHb) gene. This study subsequently aimed to examine the role of Prop-1 in the gene expression of two other porcine gonadotropin subunits, pituitary glycoprotein hormone a subunit (aGSU), and luteinizing hormone b subunit (LHb). A series of deletion mutants of the porcine aGSU (up to K1059 bp) and LHb (up to K1277 bp) promoters were constructed in the reporter vector, fused with the secreted alkaline phosphatase gene (pSEAP2-Basic). Transient transfection studies using GH3 cells were carried out to estimate the activation of the porcine aGSU and LHb promoters by Prop-1, which was found to activate the aGSU promoter of K1059/C12 bp up to 11 . 7-fold but not the LHb promoter. Electrophoretic mobility shift assay and DNase I footprinting analysis revealed that Prop-1 binds to six positions, K1038/K1026, K942/K928, K495/K479, K338/K326, K153/K146, and K131/K124 bp, that comprise the A/T cluster. Oligonucleotides of six Prop-1 binding sites were directly connected to the minimum promoter of aGSU, fused in the pSEAP2-Basic vector, followed by transfecting GH3 cells to determine the cis-acting activity. Finally, we concluded that at least five Prop-1 binding sites are the cis-acting elements for aGSU gene expression. The present results revealed a notable feature of the proximal region, where three Prop-1-binding sites are close to and/or overlap the pituitary glycoprotein hormone basal element, GATA-binding element, and junctional regulatory element. To our knowledge, this is the first demonstration of the role of Prop-1 in the regulation of aGSU gene expression. These results, taken together with our previous finding that Prop-1 is a transcription factor for FSHb gene, confirm that Prop-1 modulates the synthesis of FSH at the transcriptional level. On the other hand, the defects of Prop-1 are known to cause dwarfism and combined pituitary hormone deficiency accompanying hypogonadism. Accordingly, the present observations provide a novel view to understand the hypogonadism caused by Prop-1 defects at the molecular level through the regulatory mechanism of aGSU and FSHb gene expressions.

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“…A known target of other LHX proteins is the glycoprotein hormone-a (CGA) gene. LHX-mediated CGA gene expression depends on the presence of a LHX-binding site (PGBE) within the CGA promoter (Roberson et al, 1994). To establish direct binding of the LHX4 protein to this promoter, we performed ChIP with the anti-LHX4 antibody on SYO1 extracts.…”

Section: Coimmunoprecipitation Of Endogenous Lhx4 and Ss18-ssx Proteinsmentioning

confidence: 99%

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

et al. 2007

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As a result of the synovial sarcoma-associated t(X;18) translocation, the SS18 gene on chromosome 18 is fused to either one of the three closely related SSX genes on the X chromosome. The SS18 protein is thought to act as a transcriptional co-activator, whereas the SSX proteins are thought to act as transcriptional corepressors. The main SSX-repression domain is located in its C terminus, a domain that is retained in the respective SS18-SSX fusion proteins. Both the SS18 and SSX proteins lack DNAbinding domains. Previously, we found that the SS18 and SS18-SSX fusion proteins may be tethered to DNA targets via the SS18-interacting protein AF10. Here, we set out to isolate proteins that interact with the SSX C-terminal repression domain using a yeast two-hybrid interaction trap. Of the positive clones isolated, two corresponded to the LIM homeobox protein LHX4, a DNA-binding protein that is involved in transcription regulation. An endogenous interaction was subsequently established in mammalian cells via colocalization and coimmunoprecipitation of the respective proteins. Interestingly, the LHX4 gene was previously found to be deregulated in various human leukemias. In addition, it was previously found that LIM homeobox proteins may bind to and activate the glycoprotein-a (CGA) promoter. Using LHX4 chromatin immunoprecipitation and CGApromoter assays, we found that endogenous LHX4 binds to the CGA promoter and that LHX4-mediated CGA activation is enhanced by the SS18-SSX protein, but not by the SSX protein. Taken together, we conclude that this novel protein -protein interaction may have direct consequences for the (de)regulation of SSX and/or SS18-SSX target genes and, thus, for the development of human synovial sarcomas.

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Activation of the glycoprotein hormone alpha-subunit promoter by a LIM-homeodomain transcription factor.

Cited by 144 publications

References 58 publications

Embryonic Expression of the Luteinizing Hormone β Gene Appears to Be Coupled to the Transient Appearance of p8, a High Mobility Group-related Transcription Factor

Embryonic Expression of the Luteinizing Hormone β Gene Appears to Be Coupled to the Transient Appearance of p8, a High Mobility Group-related Transcription Factor

Pituitary transcription factor Prop-1 stimulates porcine pituitary glycoprotein hormone α subunit gene expression

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

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