Tissue-specific expression of the human growth hormone gene is conferred in part by the binding of a specific trans-acting factor.

Lefevre, Carine; Imagawa, Masayoshi; Dana, Sharon L.; Grindlay, Joan; Bodner, Mordechai; Karin, Michael

doi:10.1002/j.1460-2075.1987.tb04847.x

Cited by 216 publications

(100 citation statements)

References 47 publications

(44 reference statements)

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“…Members of the POU family are characterized by a DNA binding domain referred to as the POU domain [39]. Pit-1 is required for the terminal differentiation of somatotroph cells [40] and is responsible for the somatotroph-specific expression of GH [25]. It is interesting to note that Dlk1, a gene proposed to keep cells in an undifferentiated state [41] can repress the activity of a transcription factor known to promote terminal differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have shown that the -90 to -70 region of the GH promoter contains a binding site for the transcription factor Pit-1/GHF-1 [25]. The overlap of the Pit-1 response element with the Dlk1 responsive region strongly implies that Dlk1-mediated GH repression occurs through a Pit-1-dependent mechanism.…”

Section: A Pit-1 Response Element Is Required For Dlk1-mediated Regulmentioning

confidence: 98%

“…The overlap of the Pit-1 response element with the Dlk1 responsive region strongly implies that Dlk1-mediated GH repression occurs through a Pit-1-dependent mechanism. The GH promoter contains two separate Pit-1 response elements, a proximal site that maps to -88/-75 and a distal site that maps to -124/-111 [25]. A reporter construct that had the -130 to -65 region of the GH promoter deleted (d130-65GHp-Luc) was generated to determine if Dlk1 could regulate the activity of the GH promoter in the absence of the Pit-1 sites.…”

Section: A Pit-1 Response Element Is Required For Dlk1-mediated Regulmentioning

confidence: 99%

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Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell

Zhou

Schjeide

et al. 2007

Molecular and Cellular Endocrinology

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Delta-like protein 1 (Dlk1) is a transmembrane protein characterized by epidermal growth factor (EGF)-like repeats. Dlk1, which is also known as preadipocyte factor 1 (pref-1) because of its ability to inhibit preadipocyte differentiation, regulates the differentiation of several other cell types through unknown mechanisms. To elucidate Dlk1 functions, identification of Dlk1-regulated target genes is critical. The observation that Dlk1 is expressed in many endocrine tissues suggests that Dlk1 may have endocrine-related functions. Because Dlk1 is expressed in GH producing cells, we hypothesize that one function of Dlk1 is to regulate GH expression. We found that GH mRNA, protein, and secretion were significantly decreased in GH3 pituitary cell clones that stably express Dlk1. In contrast, Dlk1 expression was unable to alter prolactin expression. Co-transfection of GH3 cells with a GH promoter-regulated reporter gene showed that Dlk1 repressed GH promoter activity. Deletion and mutation analysis of the GH promoter indicated that Pit-1 binding sites in the GH promoter are required for Dlk1-mediated repression. Furthermore, Dlk1 expression represses Pit-1-mediated transcription when both proteins are co-expressed in MCF-7 cells. Deletion analysis of Dlk1 revealed that the ability of Dlk1 to regulate GH promoter activity is independent of both its EGF-like repeats and its ability to modulate MAP kinase activity. The observation that Dlk1 regulates GH expression identifies the first endocrine function of Dlk1, establishes GH as a Dlk1-regulated target gene, and provides a model system to facilitate studies of Dlk1-mediated signaling.

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Section: Discussionmentioning

confidence: 99%

Section: A Pit-1 Response Element Is Required For Dlk1-mediated Regulmentioning

confidence: 98%

Section: A Pit-1 Response Element Is Required For Dlk1-mediated Regulmentioning

confidence: 99%

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Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell

Zhou

Schjeide

et al. 2007

Molecular and Cellular Endocrinology

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“…It is mainly expressed in the pituitary and its expression is necessary for the normal differentiation, development and survival of three adenohypophysis cell types, thyrotrophs, somatotrophs and lactotrophs (Li et al, 1990;Simmons et al, 1990). It is also important for the proper expression of growth hormone (GH ), prolactin (PRL) (Lefevre et al, 1987;Nelson et al, 1988), thyroid-stimulating hormone (TSH ) (Li et al, 1990) and POU1F1 gene itself (Chen et al, 1990;McCormick et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of four splicing variants of ovine POU1F1 gene

Bastos

Ávila

Cravador

et al. 2006

Gene

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Expression of POU1F1 gene, a member of the POU homeodomain family of transcription factors, is necessary for normal differentiation, development and survival of three anterior pituitary cell types (thyrotrophs, somatotrophs and lactotrophs) and for the proper expression of growth hormone (GH ), prolactin (PRL), thyroid-stimulating hormone (TSH ) genes and POU1F1 gene itself. Alternative splicing forms of this gene have been reported in different species, with few functional studies. Apart from the POU1F1-Wild-type with the expected length, in this work we isolated three additional splicing variants: POU1F1-β, with a 78 bp insert in the trans-activation domain; POU1F1-γ that lacks exon 3 and POU1F1-δ that lacks exons 3, 4 and 5. Four different protein isoforms were also detected by Western blot in the sheep pituitary tissue. Functional assays were performed to study the trans-activation of GH and PRL promoters by the splicing variants. Regarding the PRL promoter, the β variant presented only 12% of the Wild-type trans-activation capacity. Variants γ and δ showed no capacity to trans-activate PRL promoter. Both γ and δ variants acted as repressors of Wt, reducing significantly the trans-activation made by Wt alone ( p < 0.05). Concerning the GH promoter, the β variant presented a trans-activation capacity 10% higher than Wt. Wt and β variants strongly interact in the activation of GH promoter doubling the trans-activation potential of Wt. Variants γ and δ showed no capacity to trans-activate the GH promoter and both acted as repressors, reducing significantly ( p < 0.001) the trans-activation performed by Wt. This work presents, for the first time, the characterization of four splicing forms of Ovis aries POU1F1 gene.

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“…Most exert their regulatory effects by binding specific nuclear regulatory proteins. Some of these proteins, such as GC2 [2,31 or its human homolog GHF2 [4], both later found to correspond to the well-known transcription factor Spl [5,61, clearly act as positive regulators of rGH gene transcription and are produced by numerous cell types. Others, such as Pit-1 [7, 81 (also called GC1 or GHFl) or the thyrotroph embryonic factor (TEF) [9], probably corresponding to a factor termed GC3 [2], also exert positive effects on GH gene transcription but are produced in a cell-specific manner only by pituitary cells.…”

mentioning

confidence: 99%

The 30‐kDa rat liver transcription factor nuclear factor 1 binds the rat growth‐hormone proximal silencer

Roy

Guérin

1994

European Journal of Biochemistry

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Transcription of the gene encoding rat growth hormone is under the influence of cis-acting negative regulatory elements termed silencers. We showed previously that one such element, designated the rat growth hormone proximal silencer-1 site, binds a nuclear protein, the nuclear-factor-1-like protein that is probably a member of the CAAT transcription factor/nuclear-factor-1 (CTF/ NF-I) family of transcription factors. This nuclear protein possesses DNA-binding activity as well as biochemical properties similar to those reported for the 30-kDa rat liver form of nuclear factor 1 (NF1-L). Results from both gel mobility supershift assays and Westem-blot analyses, performed in combination with a polyclonal antibody directed against the DNA-binding domain of NF1 -L, indicated that rat liver nuclear factor 1 might indeed correspond to one of the transcription factors interacting with the rat growth-hormone proximal silencer element. Further experiments using gel mobility shift assays also indicated that, as for NF1-L, multiple proteins among the 52-66-kDa CTFNF-I isoforms from human HeLa cells also possess the ability to bind the rat growth-hormone silencer.

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Tissue-specific expression of the human growth hormone gene is conferred in part by the binding of a specific trans-acting factor.

Cited by 216 publications

References 47 publications

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Identification and characterization of four splicing variants of ovine POU1F1 gene

The 30‐kDa rat liver transcription factor nuclear factor 1 binds the rat growth‐hormone proximal silencer

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