The growth hormone-binding protein is a location-dependent cytokine receptor transcriptional enhancer.
In the rat, a growth hormone-binding protein (GHBP) exists that is derived from the growth hormone (GH) receptor gene by an alternative mRNA splicing mechanism such that the transmembrane and intracellular domains of the GH receptor are replaced by a hydrophilic carboxyl terminus. In isolation, the GHBP is inactive, although it does compete with the receptor for ligand binding in the extracellular space and therefore inhibits the cellular response to GH. The GHBP is also located intracellularly and is translocated to the nucleus upon ligand stimulation. We show here that endogenously produced GHBP, in contrast to exogenous GHBP, was able to enhance the STAT5-mediated transcriptional response to GH. Interestingly, when the GHBP was targeted constitutively to the nucleus by the addition of the nuclear localization sequence of the SV40 large T antigen, greater enhancement of STAT5-mediated transcription was obtained. The transcriptional enhancement did not require GH per se and was not specific to the GH receptor, since similar enhancement of STAT5-mediated transcription by nuclear localized GHBP was obtained with specific ligand stimulation of both prolactin and erythropoietin receptors. Thus, the GHBP exerts divergent effects on STAT5-mediated transcription depending on its cellular location. The use of a soluble cytokine receptor as a location-dependent transcriptional enhancer and the ligand-independent involvement of the extracellular domain of a polypeptide ligand receptor in intracellular signal transduction provide additional novel mechanisms of transcriptional control.
Graichen
Ralph
R
Institute of Molecular and Cell Biology, 117609 Singapore, Republic of Singapore.
Sandstedt
Jonas
J
Goh
Eyleen L K
EL
Isaksson
Olle G P
OG
Törnell
Jan
J
Lobie
Peter E
PE
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017398:Alternative Splicing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D017930:Genes, Reporter; D005822:Genetic Vectors; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D008894:Milk Proteins; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011915:Rats, Inbred BUF; D018121:Receptors, Cytokine / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019382:Human Growth Hormone; D008156:Luciferases; C051815:somatotropin-binding protein