Molecular Biology of the Pituitary Gonadotropins

Gharib, Soheyla D.; Wierman, Margaret E.; Shupnik, Margaret A.; Chin, William W.

doi:10.1210/edrv-11-1-177

Cited by 649 publications

(337 citation statements)

References 152 publications

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“…Placenta-specific transcriptional controls fall into two broad categories: first, they may share the same promoter as other tissues, but utilize placenta-specific enhancers or upstream elements as observed for glycoprotein hormone ␣ subunit, CS-B, adenosine deaminase (ADA), and leptin genes (28,29,32,38,39); second, they may utilize both placenta-specific promoters and enhancers, as previously shown for the aromatase gene (33) and as we now show for the LIFR gene.…”

Section: Discussionsupporting

confidence: 54%

“…A composite enhancer (Ϫ180/Ϫ111 bp) of the glycoprotein hormone ␣ subunit gene promoter is responsible for its placental expression rather than pituitary gonadotropic or thyrotropic expression (29). This enhancer was composed of two CREs and an upstream regulatory element (URE) (40,41), whereas URE could be further subdivided into three overlapping sites, ␣ activator element, TSE, and URE1 (42).…”

Section: Discussionmentioning

confidence: 99%

“…Characterization of Human LIFR Placenta-specific Enhancerenhancer was active in choriocarcinoma JEG-3 and JAR cells, and inactive in cell lines derived from nonplacental tissues such as liver, bone marrow, thyroid, breast, and lung (25). At that time, we did not specifically test pituitary cell lines, but placental and pituitary cells share considerable similarities for transcriptional regulation of several genes, including growth hormone, glycoprotein hormone ␣ subunit, chorionic somatomammotropin B (CS-B, or placental lactogen, PL) (27)(28)(29). We therefore chose several available pituitary cell lines, namely ACTH-producing AtT20 and growth hormone secreting GH4 and GC cell lines to further test the specificity of the cloned LIFR gene enhancer and two LIFR promoters.…”

Section: Methodsmentioning

confidence: 99%

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Functional Map of a Placenta-specific Enhancer of the Human Leukemia Inhibitory Factor Receptor Gene

Wang

Melmed

1998

Journal of Biological Chemistry

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We recently reported a placenta-specific enhancer in the human leukemia inhibitory factor receptor (LIFR) gene and now show detailed characterization of the 226-base pair enhancer (؊4625/؊4400 nucleotides). Four of twenty-two mutants in linker analysis showed reduced promoter activities to 45, 30, 10, and 10%, respectively. Specific binding of region A (؊4617/؊4602) with nuclear extract was competed by a known Oct-1 oligo and supershifted by Oct-1 antibody. Specific binding of region B (؊4549/؊4535) was competed by a GATA oligo, but could not be supershifted by four GATA antibodies. Nevertheless, mutagenesis showed that critical bases in region B were identical to the GATA core motif, indicating that region B may bind to a novel GATA family transcription factor. The other two adjacent regions designated as region C (؊4464/؊4445) showed no known consensus binding sites, and their specific placental JEG-3 nuclear extract binding was not evident in nonplacental nuclear extracts and was not competed by a trophoblast specific element (TSE), indicating that region C is a novel placenta-specific element (PSE, CATTTCCTGAACTAGTT-TTT). Footprinting localized the binding boundary of PSE-binding protein (PSEB), and three Gs were found to be important for specific PSE binding. UV cross-linking showed that PSEB had a molecular mass of ϳ160 kDa, substituting the PSE with two previously reported placenta elements TSE or chorionic somatomammotropin enhancer factor 1 (CSEF-1) motifs resulted in markedly different promoter activities, indicating that PSEB is indeed different from TSE binding protein or CSEF-1. These results are the first demonstration that a novel PSE is the major element for placenta-specific enhancer activity in human LIFR gene.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Functional Map of a Placenta-specific Enhancer of the Human Leukemia Inhibitory Factor Receptor Gene

Wang

Melmed

1998

Journal of Biological Chemistry

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“…An atypical member of the rhodopsin-like family of GPCR, the GnRHR is located on the cell surface of pituitary gonadotropes (14 -16). The binding of the hypothalamic decapeptide GnRH to the pituitary GnRHR not only stimulates but is obligatory for the synthesis and secretion of luteinizing hormone (LH) (15,16). In the absence of GnRH input to the pituitary gland, LH production and, consequently, gonadal function in mammals ceases (17,18).…”

mentioning

confidence: 99%

Constitutive Localization of the Gonadotropin-releasing Hormone (GnRH) Receptor to Low Density Membrane Microdomains Is Necessary for GnRH Signaling to ERK

Navratil

Bliss

Berghorn

et al. 2003

Journal of Biological Chemistry

134

105

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Specialized membrane microdomains known as lipid rafts are thought to contribute to G-protein coupled receptor (GPCR) signaling by organizing receptors and their cognate signaling molecules into discrete membrane domains. To determine if the GnRHR, an unusual member of the GPCR superfamily, partitions into lipid rafts, homogenates of ␣T3-1 cells expressing endogenous GnRHR or Chinese hamster ovary cells expressing an epitope-tagged GnRHR were fractionated through a sucrose gradient. We found the GnRHR and c-raf kinase constitutively localized to low density fractions independent of hormone treatment. Partitioning of c-raf kinase into lipid rafts was also observed in whole mouse pituitary glands. Consistent with GnRH induced phosphorylation and activation of c-raf kinase, GnRH treatment led to a decrease in the apparent electrophoretic mobility of c-raf kinase that partitioned into lipid rafts compared with unstimulated cells. Cholesterol depletion of ␣T3-1 cells using methyl-␤-cyclodextrin disrupted GnRHR but not c-raf kinase association with rafts and shifted the receptor into higher density fractions. Cholesterol depletion also significantly attenuated GnRH but not phorbol ester-mediated activation of extracellular signal-related kinase (ERK) and c-fos gene induction. Raft localization and GnRHR signaling to ERK and c-Fos were rescued upon repletion of membrane cholesterol. Thus, the organization of the GnRHR into low density membrane microdomains appears critical in mediating GnRH induced intracellular signaling.

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“…Luteinizing hormone (LH) is a pituitary‐derived heterodimeric glycoprotein that shares the common α‐subunit with FSH, hCG and TSH, but possesses a unique β‐subunit conferring the biological specificity of LH (Pierce & Parsons, 1981; Gharib et al ., 1990). In both genders, LH is essential for reproduction and its action is mediated through binding to its receptors in testes and ovaries.…”

Section: Introductionmentioning

confidence: 99%

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

et al. 2015

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SummaryLuteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V‐LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH β‐subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V‐LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V‐LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 ± 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 ± 5.9 years). V‐LH was detected by genotyping of the underlying DNA polymorphisms using PCR‐RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta‐analysis. No significant difference was detected between young men and infertility patients for the V‐LH allele frequency (11.0 vs. 9.3%, respectively). V‐LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta‐analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V‐LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB ‐211G/T, FSHR Asn680Ser, FSHR ‐29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V‐LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V‐LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned.

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Molecular Biology of the Pituitary Gonadotropins

Cited by 649 publications

References 152 publications

Functional Map of a Placenta-specific Enhancer of the Human Leukemia Inhibitory Factor Receptor Gene

Functional Map of a Placenta-specific Enhancer of the Human Leukemia Inhibitory Factor Receptor Gene

Constitutive Localization of the Gonadotropin-releasing Hormone (GnRH) Receptor to Low Density Membrane Microdomains Is Necessary for GnRH Signaling to ERK

‘Carriers of V‐LH among 1593 Baltic men have significantly higher serum LH’

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