Ligand-dependent and -independent effects of splice variant 1 of growth hormone-releasing hormone receptor.
Existing evidence indicates that, in addition to its neuroendocrine action, growth hormone-releasing hormone (GHRH) acts directly on several nonpituitary tissues, especially neoplasms, and stimulates cell proliferation. We have recently reported that a splice variant of the receptor (SV1) is expressed in various normal tissues and particularly in tumor tissues, producing mitogenic effects on GHRH binding. By using HEC-1A human endometrial carcinoma cells, which express endogenous SV1, we show that, in addition to its ability to mediate the mitogenic effects of GHRH, SV1 also possesses relatively high intrinsic, ligand-independent activity. By using an antisense RNA-based approach we found that SV1 ablation reduces the efficacy of colony formation and the rate of cell proliferation of HEC-1A cells in the absence of exogenous GHRH, and decreases their sensitivity to GHRH when the neurohormone is added to the culture media. This ligand-independent stimulation of cell proliferation appears to be a characteristic property of the truncated form of the receptor, because the expression of SV1 and not of the full-length GHRH receptor stimulated the proliferation of 3T3 fibroblasts in the absence of exogenous GHRH, whereas both forms mediated the proliferative effects of GHRH. Evaluation of 21 specimens of human primary endometrial carcinoma for expression of SV1 by immunohistochemistry indicated that in contrast to the GHRH receptor, which is absent, SV1 is expressed in approximately 43% of the specimens. These findings indicate that SV1 can operate in a ligand-independent as well as a ligand-dependent manner. The overexpression of this form of GHRH receptor may be associated with carcinogenesis.
Kiaris
Hippokratis
H
Department of Biological Chemistry,Medical School, University of Athens, 115 27 Athens, Greece. hkiaris@med.uoa.gr
Chatzistamou
Ioulia
I
Schally
Andrew V
AV
Halmos
Gabor
G
Varga
Jozsef L
JL
Koutselini
Helen
H
Kalofoutis
Anastasios
A
D016475:3T3 Cells; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000818:Animals; D002277:Carcinoma / Q000473:pathology; D002455:Cell Division; D003470:Culture Media / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D051379:Mice; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000096:biosynthesis* / Q000235:genetics*; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000096:biosynthesis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured
D003470:Culture Media; D008024:Ligands; D016376:Oligonucleotides, Antisense; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D012313:RNA; C048250:somatotropin releasing hormone receptor