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| A: Human LHR gene organization. B: 5' flanking regulatory domains and the 176 bp promoter with its functional domains (Geng et al., 1999; Dufau and Tsai-Morris, 2007). B-I Promoter associated transcription factor Sp1 bound to cognate DNA sites, Sp1-I and Sp1-II, constitutively (Geng et al., 1999). Co-repressor complex (HDAC/mSin3A) associates with Sp1-I (Zhang et al., 2000; Zhang et al., 2001; Zhang et al., 2002; Zhang et al., 2003; Zhang et al., 2004). Upstream inhibitory domain (ERE-DR Motif) that bind orphan receptors EAR2 and EAR3, inhibitory and TR4, stimulatory (arrows). B-II, Histone deacetylase inhibitor (TSA)-induced LHR transcriptional activation through chromatin changes cause release of cell specific phosphatases (PP1, PP2A) (Zhang et al 2008). This permits phosphorylation of Sp1 at S641 via PI3K/PKCzeta (Zhang, 2006), and the release of repressor p107 and corepressor HDAC/mSin3A (Zhang et al., 2008; Dufau et al., 2010). Recruitment of Positive Coactivator4 PC4 induced by changes in chromatin structure is required for transcriptional activation that follows recruitment of TFIIB and Pol II (Liao et al., 2008; Liao et al., 2011). PC4 might function as a linker to bridge Sp1 to PIC through a not-yet identified protein(s) (red circle). Triangle: multiple transcriptional start sites. PA: polyadenylation sites. Open arrow, up: activation, down: inhibition. ERE: estrogen response element. DR: direct repeat. OR: orphan receptor. Sp1 I, Sp1 II: Sp1 sites. PIC: preinitiation complex. |
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Description | Human LHR gene is encoded by a single copy gene. The human LHR gene (> 80 Kb) consists of 11 coding exons separated by 10 introns (Atger et al., 1995). At least seven alternatively spliced variants of the hLHR were reported (deletion of exon 8 or 9 or 10, or partial deletion of exon 11 combined with or without deletion of exon 9, and insertion of exon 6A) (Laue et al., 1996; Gromoll et al., 2000; Madhra et al., 2004; Kossack et al., 2008). |
Transcription | Multiple LHR mRNA transcriptional start sites are located within the -176 bp TATA-less 5' flanking promoter domain (Geng et al., 1999; Dufau and Tsai-Morris, 2007). Additional upstream transcriptional start sites (> -176 bp) were identified in human testicular mRNA and human choriocarcinoma JAR cell. EREhs (-161 to -171 bp) and upstream sequences (-177 to -2056 bp) are inhibitory. Activation of the human LHR promoter through Sp1 and Sp3 factors at Sp1 sites is negatively regulated by cross-talk among the transcription factors EAR3/COUP-TFI, Sp1, TFIIB, and independently by histone deacetylase-mSin3A co-repressor complex, p107 repressor at the Sp1 I site (review: Zhang and Dufau, 2004; Dufau and Tsai-Morris, 2007; Dufau et al., 2010). |
Pseudogene | No known pseudogenes. |
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| Schematic representation of human LHR variants, as deduced from the alternative splicing of the transcripts. Arrow-head: LQ insertion. Exon 6A resides in intron 6, transcripts are terminated by a poly A tail (terminal) or via internal splice sites to produce a 150 bp (short) or 207 bp (long) internal exon and continue to exon 7-11 (Kossack et al., 2008). In all cases a truncated LHR protein of 209 aa is generated. Arrow: Stop codon. |
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Description | The cDNA for the human LHR encodes 699 amino acids (Minegishi et al., 1990; Jia et al., 1991). The receptor is composed of two functional units: the extracellular hormone-binding domain and the seven-membrane transmembrane/cytoplasmic module, which is the anchoring unit that transduces the signal initiated in the extracellular domain and couples to G proteins. The large extracellular domain binds LH and hCG with high affinity. |
Expression | LHR is predominantly expressed in gonads. The LHR has also been identified in several non-gonadal tissues (review, Rao, 2001), including human nonpregnant uterus, placenta (Reshef et al., 1990), fallopian tubes (Lei et al., 1993), uterine vessels, (Toth et al., 1994), umbilical cord (Rao et al., 1993), brain (Lei et al., 1993), breast (Meduri et al., 1997; Carlson et al., 2004), and adrenal gland (Lehmann et al., 1975). |
Localisation | Predominantly localized in the cell membrane. |
Function | The LHR mediates gonadotropin signaling and triggers intracellular responses that participate in gonadal maturation and function, as well as in the regulation of steroidogenesis and gametogenesis (review, Richards et al., 1988; Dufau, 1998; Dufau and Tsai-Morris, 2007). Luteinizing hormone through its surface receptors on the Leydig cell maintains general metabolic processes and steroidogenic enzymes to regulate the production of androgens. In the ovary, LH promotes follicular development, at stages beyond early antral follicles including the formation of preovulatory follicles and corpora lutea. Target disruption of LH receptor in the mouse revealed a normal prenatal development and lack of postnatal sexual development (Lei et al., 2001; Zhang et al., 2001). This indicated that LH/LHR action in male rodents is not required or can be compensated by other hormone(s) or factors during fetal life which is in sharp contrast with the situation in the human. The major changes in sexual development observed after birth in the mouse included significant inhibition of testis growth and descent and of sex accessory organs. Testosterone could partially restore spermatogenesis and fertility (Pakarainen et al., 2005; Yuan et al., 2006). |
Homology | The percent identity below represents identity using Global pairwise alignment function (GAP). M. musculus: 83,2 R. Norvegicus: 85,2 D. Melanogaster: 40,1 A. gambiae: 39,7 C. elegans: 30,7 |
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