Inhibition of signal transduction by a splice variant of the growth hormone-releasing hormone receptor expressed in human pituitary adenomas.
We have previously shown that some of human growth hormone (GH)-producing pituitary adenomas preferentially express a larger transcript of GH-releasing hormone (GHRH) receptor (GHRH-R). This transcriptional variant is presumed to be produced by alternative messenger RNA splicing and contains premature stop codon in frame, predicted to yield a truncated GHRH-R. Functional expression study indicated that the variant receptor was unable to transduct GHRH signals. To determine the functional relationship between the splice-variant and the wild-type GHRH-R, the expression vector for the variant GHRH-R transcript was transfected into COS-7 cells together with or without that for the wild GHRH-R transcript. In cells transfected with both GHRH-R expression vectors, GHRH-dependent cyclic adenosine monophosphate (cAMP) induction was decreased to 39% of that in the cells transfected with the wild-type GHRH-R expression vector alone. This inhibition was found to be irrespective of the concentration (10(-8) to 10(-5) mol/L) of GHRH. These findings suggest that the splice variant form of GHRH-R functions as a dominant-negative modulator in GHRH-induced cellular signaling.
Department of Medicine III, Osaka University Medical School, Suita-City, Japan.
T
T
Motomura
K
K
Hashimoto
M
M
Koga
N
N
Arita
T
T
Hayakawa
T
T
Kishimoto
S
S
Kasayama
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005822:Genetic Vectors / Q000378:metabolism; D006801:Humans; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection
D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; C048250:somatotropin releasing hormone receptor