The Human Growth Hormone Gene Cluster Locus Control Region Supports Position-independent Pituitary- and Placenta-specific Expression in the Transgenic Mouse

Su, Yongxuan; Liebhaber, Stephen A.; Cooke, Nancy E.

doi:10.1074/jbc.275.11.7902

Cited by 80 publications

(93 citation statements)

References 38 publications

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“…The expression of the hGH-V gene is largely restricted to the placenta by placenta-specific enhancers and pituitary-specific repressors (Eberhardt et al 1996), although limited expression in other tissues, including lymphoid tissues (Melen et al 1997), normal and tumorous pituitary glands (Scippo et al 1991, Nickel & Cattini 1992) and the testis (Untergasser et al 1998), has been detected. The transcriptional regulation of the hGH-V gene has been the subject of several recent reviews (Eberhardt et al 1996, Su et al 2000 and will not be discussed here in detail.…”

Section: Pregnancy In Primatesmentioning

confidence: 99%

“…This membranebound protein may interact with GH/prolactin receptors on the cell surface, resulting in receptor dimerization/ activation and/or in receptor inhibition (Untergasser et al 2000). The transcriptional regulation of the hCS genes has been well reviewed recently (Eberhardt et al 1996, Su et al 2000 and will not be discussed here in detail.…”

Section: Chorionic Somatomammotropinmentioning

confidence: 99%

“…The pregnancy-induced elevation in circulating GH concentrations reflects increased activity of the pituitary GH gene within the pituitary gland, since immunoreactive GH is undetectable in the plasma of pregnant hypophysectomized rats (Carlsson et al 1990b). Moreover, the pituitary GH gene is the only member of the GH gene cluster in nonprimates (Su et al 2000). Although placental lactogen genes have been detected in rodents and cattle, these genes are more closely related to prolactin than to GH and evolved after the phylogenetic separation of primates (Eberhardt et al 1996, Ishibashi & Imai 1999.…”

Section: Pregnancy In Non-primatesmentioning

confidence: 99%

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GH as a co-gonadotropin: the relevance of correlative changes in GH secretion and reproductive state

Hull

Harvey

2002

Journal of Endocrinology

104

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It is now well established that exogenous GH promotes sexual maturation and reproductive function. The possibility that this may reflect physiological actions of endogenous GH has, however, rarely been considered. Correlative changes in GH secretion and reproductive state (puberty, pregnancy, lactation, menopause and ovarian cycles) are thus the primary focus of this review. GH secretion is, for instance, elevated during major transitions in reproductive status such as puberty and pregnancy. In some cases, augmented circulating GH levels are paired with hepatic GH resistance. This interaction may permit selective activation of gonadal responses to GH without activating IGF-I-mediated systemic responses. This selective activation may also be mediated by autocrine, paracrine or intracrine GH actions, since GH is also synthesized in reproductive tissues. Correlative changes in GH secretion and reproductive state may be mediated by events at the hypothalamic, pituitary and gonadal level. In addition to direct effects on gonadal function, GH may influence reproductive activity by increasing gonadotropin secretion at the hypothalamic and pituitary level and by enhancing gonadotropin responsiveness at the gonadal level. The close association between reproductive status and the somatotrophic axis supports the physiological importance of GH in reproductive function.

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Section: Pregnancy In Primatesmentioning

confidence: 99%

Section: Chorionic Somatomammotropinmentioning

confidence: 99%

Section: Pregnancy In Non-primatesmentioning

confidence: 99%

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GH as a co-gonadotropin: the relevance of correlative changes in GH secretion and reproductive state

Hull

Harvey

2002

Journal of Endocrinology

104

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“…The five HSs together comprise a putative hGH locus control region (LCR). Significantly, when hGH-N transgene DNA is extended to encompass the entire set of HSs, hGH gene expression is rendered pituitary-specific, copy number-dependent, and robust in every line generated (8,10). This establishment of an autonomous chromatin domain that supports high-level expression from a linked transgene irrespective of the site of integration in the mouse genome fulfills the most rigorous operational definition of an LCR (11,12).…”

mentioning

confidence: 92%

Specification of unique Pit-1 activity in the hGH locus control region

Shewchuk

Liebhaber

Cooke

2002

Proc. Natl. Acad. Sci. U.S.A.

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The human GH (hGH) gene cluster is regulated by a remote 5 locus control region (LCR). HSI, an LCR component located 14.5 kb 5 to the hGH-N promoter, constitutes the primary determinant of highlevel hGH-N activation in pituitary somatotropes. HSI encompasses an array of three binding sites for the pituitary-specific POU homeodomain factor Pit-1. In the present report we demonstrate that all three Pit-1 sites in the HSI array contribute to LCR activity in vivo. Furthermore, these three sites as a unit are fully sufficient for position-independent and somatotrope-restricted hGH-N transgene activation. In contrast, the hGH-N transgene is not activated by Pit-1 sites native to either the hGH-N or rat (r)GH gene promoters. These findings suggest that the structures of the Pit-1 binding sites at HSI specify distinct chromatin-dependent activities essential for LCR-mediated activation of hGH in the developing pituitary.T he expression of the GH gene has been the focus of intense study over the past 20 years. A consistent feature of all GH promoters is a highly conserved pair of AT-rich binding sites for the pituitary-restricted trans factor Pit-1 (1, 2). Between these two Pit-1 elements is a conserved binding site for a ubiquitous DNA-binding protein, Zn15 (3). Additional, less conserved cis elements have been identified in the vicinity of the GH promoter in various species. Studies carried out in vitro and in celltransfection models indicate that the Pit-1 binding sites are essential to the expression of the GH gene (4-6). However, studies of human (h)GH gene expression in transgenic settings demonstrate that promoter-proximal elements including the Pit-1 sites are not sufficient to activate hGH gene expression in vivo. For example, in transgenic mice, the hGH gene with its full promoter and as much as 7.5 kb of 5Ј-flanking sequences is either not expressed or expressed at very low levels and does not maintain somatotrope cell specificity (7,8). These data suggest that regulatory sequences quite distant from the hGH gene are necessary to establish a transcriptionally active chromatin domain.The hGH gene cluster spans 48 kb on chromosome 17q22-24 (for details see Fig. 1; ref. 9). This cluster contains the pituitaryexpressed hGH-N and four genes expressed in the placenta:, and hCS-B (Fig. 1). A search for distal regulatory determinants of hGH-N gene expression revealed DNaseI hypersensitive sites (HSs) in pituitary chromatin and a partially overlapping set of HSs in placental chromatin (ref. 8; Fig. 1). HSI and HSII, located between Ϫ14.5 kb and Ϫ15 kb relative to the hGH-N promoter, are specific to pituitary chromatin. HSIV, at Ϫ30 kb, is specific to the placenta and HSIII and HSV, at Ϫ27.5 and Ϫ32 kb, respectively, are shared in both expressing tissues. The five HSs together comprise a putative hGH locus control region (LCR). Significantly, when hGH-N transgene DNA is extended to encompass the entire set of HSs, hGH gene expression is rendered pituitary-specific, copy number-dependent, and robust in every line generat...

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“…To test this, we made use of a construct containing the extensively characterized human growth hormone (hGH) promoter and locus control region (LCR) (22). The hGH LCR reliably directs position-independent, copy number-dependent transgene expression in the pituitary somatotrophs of transgenic mice.…”

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confidence: 99%

Activation of CD8 T Cells by Antigen Expressed in the Pituitary Gland

Jersey¹,

Carmignac

Barthlott

et al. 2002

The Journal of Immunology

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Ag expressed exclusively in the anterior pituitary gland and secreted locally by pituitary somatotrophs can gain access to the MHC class I presentation pathway and activate CD8 T cells. Influenza nucleoprotein (NP) was expressed as a transgene under the control of the human growth hormone (GH) locus control region. Activation of monoclonal F5 CD8 T cells specific for NP resulted in spontaneous autoimmune pathology of the pituitary gland in mice transgenic for both NP and the F5 TCR. Destruction of somatotrophs resulted in drastically reduced GH levels in adult mice and a dwarf phenotype. Adoptive transfer of F5 T cells into NP-transgenic hosts resulted in full T cell activation, first demonstrable in regional lymph nodes, followed by their migration to the pituitary gland. Despite the presence of activated, IFN-γ-producing CD8 T cells in the pituitary gland and a slight reduction in pituitary GH levels, no effect on growth was observed. Thus, CD8 T cells have access to the neuroendocrine system and get fully activated in the absence of CD4 help, but Ag recognition in this location causes autoimmune pathology only in the presence of excessive CD8 T cell numbers.

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The Human Growth Hormone Gene Cluster Locus Control Region Supports Position-independent Pituitary- and Placenta-specific Expression in the Transgenic Mouse

Cited by 80 publications

References 38 publications

GH as a co-gonadotropin: the relevance of correlative changes in GH secretion and reproductive state

GH as a co-gonadotropin: the relevance of correlative changes in GH secretion and reproductive state

Specification of unique Pit-1 activity in the hGH locus control region

Activation of CD8 T Cells by Antigen Expressed in the Pituitary Gland

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