SFE2004 Oral Communications Young Endocrinologist Session (7 abstracts)
Proliferative effects of ghrelin and desoctanoyl ghrelin are independent of the growth hormone secretagogue receptor (GHS-R)
VB Marsh 1 , B Kola 1 , M Hanson 1 , M Emery 1 , M Musat 1 , S Bonner 1 , S Khalaf 1 , D Norman 2 , AB Grossman 1 & M Korbonits 1
1Department of Endocrinology, Endocrine Oncology, St. Bartholomew's Hospital, London, UK; 2Argenta Discovery Ltd, Flex Meadow, Harlow, UK.
Background: Ghrelin was recently discovered as the natural ligand for the G protein-coupled growth hormone secretagogue receptor and induces GH release through GHS-R1a. The octanoylation of its third serine residue is responsible for GH release and receptor binding. A variant of ghrelin devoid of this modification, desoctanoyl-ghrelin, can neither bind to the receptor nor induce GH release. Ghrelin has also been shown to effect cellular proliferation, being pro-proliferative in some cell lines and anti-proliferative in others. However it has been reported that desoctanoyl-ghrelin also shares this property and our previous data has shown that indeed desoctanoyl-ghrelin is able to stimulate proliferation in the rat GH3 pituitary cell line. We therefore sought to investigate whether these proliferative effects are mediated by the GHS-R1a or not.
Aims: To investigate the effect of ghrelin and desoctanoyl-ghrelin on the proliferation of two Chinese hamster ovary cell lines, one naturally devoid of the GHS-R1a (CHO-K1) and one transfected with the GHS-R1a (CHO-GHSR).
Methods: The presence of the GHS-R1a was determined using RT-PCR. Cells were treated with ghrelin and desoctanoyl-ghrelin, using EGF as the positive control; proliferation was assessed by the degree of[H3]-Thymidine incorporation, and MAPK pathway activation by immunoblotting for p-ERK1/2.
Results: GHS-R1a expression was detected in the CHO-GHSR cells but not in the CHO-K1. Ghrelin at 10-9M caused an increase in [H3]-]-Thymidine incorporation compared to untreated controls in both transfected and untransfected cells: CHO-K1 (145%±15,P<0.01); CHO-GHSR cells (143%±4,P<0.0001). Desoctanoyl-ghrelin at 10-9M also caused an increase in [H3]-]-Thymidine incorporation: CHO-K1 (148%±15,P<0.01); CHO-GHSR (123%±3,trend); compared to untreated controls. Ghrelin and desoctanoyl-ghrelin also showed activation of p-ERK1/2 in immunoblotting analysis compared to untreated controls in both CHO-K1 and CHO-GHSR cells.
Conclusion: Our data render it highly probable that the pro-proliferative effects of ghrelin and desoctanoyl-ghrelin are exerted at a receptor other than the classical GHS-R1a.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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