The human neuroendocrine thyrotropin-releasing hormone receptor promoter is activated by the haematopoietic transcription factor c-Myb.
Thyrotropin-releasing hormone (TRH) receptor (TRHR) is a G-protein-coupled receptor playing a crucial role in the anterior pituitary where it controls the synthesis and secretion of thyroid-stimulating hormone and prolactin. Its widespread presence not only in the central nervous system, but also in peripheral tissues, including thymus, indicates other important, but unknown, functions. One hypothesis is that the neuropeptide TRH could play a role in the immune system. We report here that the human TRHR promoter contains 11 putative response elements for the haematopoietic transcription factor c-Myb and is highly Myb-responsive in transfection assays. Analysis of Myb binding to putative response elements revealed one preferred binding site in intron 1 of the receptor gene. Transfection studies of promoter deletions confirmed that this high-affinity element is necessary for efficient Myb-dependent transactivation of reporter plasmids in CV-1 cells. The Myb-dependent activation of the TRHR promoter was strongly suppressed by expression of a dominant negative Myb-Engrailed fusion. In line with these observations, reverse transcriptase PCR analysis of rat tissues showed that the TRHR gene is expressed both in thymocytes and bone marrow. Furthermore, specific, high-affinity TRH agonist binding to cell-surface receptors was demonstrated in thymocytes and a haematopoietic cell line. Our findings imply a novel functional link between the neuroendocrine and the immune systems at the level of promoter regulation.
Matre
Vilborg
V
Department of Biochemistry, University of Oslo, P.O. Box 1041 Blindern, Norway. vilborg.matre@biokjemi.uio.no
Høvring
Per I
PI
Fjeldheim
Ase-Karine
AK
Helgeland
Lars
L
Orvain
Christophe
C
Andersson
Kristin B
KB
Gautvik
Kaare M
KM
Gabrielsen
Odd S
OS
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007438:Introns; D009490:Neurosecretory Systems / Q000378:metabolism / Q000502:physiology; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D020598:Proto-Oncogene Proteins c-myb; D012333:RNA, Messenger; D018025:Receptors, Thyrotropin-Releasing Hormone