Structural and functional organization of the gene encoding the human thyrotropin-releasing hormone receptor.
The thyrotropin-releasing hormone (TRH) receptor (TRHR) is widely distributed throughout the central and peripheral nervous systems. In addition to its role in controlling the synthesis and secretion of thyroid-stimulating hormone and prolactin from the anterior pituitary, TRH is believed to act as a neurotransmitter as well as a neuromodulator. We have isolated genomic lambda and P1-derived artificial chromosome clones encoding the human TRHR. The gene was found to be 35 kb with three exons and two introns. A 541-bp intron 1 (-629 to -89 relative to the translation start site) is conserved between human and mouse. A large intron 2 of 31 kb disrupts the open reading frame (starting in position +790) in the sequence encoding the supposed junction between the third intracellular loop and the putative sixth transmembrane domain. A similar intron was found in chimpanzee and sheep but not in rat and mouse. Promoter analysis of upstream regions demonstrated cell type-specific reporter activation, and sequencing of 2.5 kb of the promoter revealed putative cis-acting regulatory elements for several transcription factors that may contribute to the regulation of the TRHR gene expression. Functional analysis of potential response elements for the anterior pituitary-specific transcription factor Pit-1 revealed cell type-specific binding that was competed out with a Pit-1 response element from the GH gene promoter.
Matre
V
V
Institute of Medical Biochemistry, University of Oslo, Norway.
Høvring
P I
PI
Orstavik
S
S
Frengen
E
E
Rian
E
E
Velickovic
Z
Z
Murray-McIntosh
R P
RP
Gautvik
K M
KM
D020121:5' Untranslated Regions / Q000235:genetics; D000236:Adenoma; D000818:Animals; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000502:physiology; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010911:Pituitary Neoplasms; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D012756:Sheep; D013045:Species Specificity; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000502:physiology
D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C494187:POU1F1 protein, human; D018025:Receptors, Thyrotropin-Releasing Hormone; D050817:Transcription Factor Pit-1; D014157:Transcription Factors