Document Detail


Human growth hormone: 45-kDa isoform with extraordinarily stable interchain disulfide links has attenuated receptor-binding and cell-proliferative activities.
MedLine Citation:
PMID:  20472479     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Human growth hormone (hGH) is a complex mixture of molecular isoforms. Gaps in our knowledge exist regarding the structures and biological significances of the uncharacterized hGH molecular variants. Mercaptoethanol-resistant 45-kDa human growth hormone (MER-45 kDa hGH) is an extraordinarily stable disulfide-linked hGH homodimer whose biological significance is unknown.
OBJECTIVES: To elucidate the pharmacokinetic abilities of dimeric MER-45-kDa hGH to bind to GH and prolactin (PRL) receptors and to elucidate its abilities to stimulate cell proliferation in lactogen-induced and somatogen-induced in vitro cell proliferation bioassays.
DESIGN: The binding of MER-45-kDa hGH to GH and PRL receptors was tested in radioreceptor assays (RRAs). Competitive displacements of [(125)I]-bovine GH from bovine liver membranes, [(125)I]-ovine PRL from lactating rabbit mammary gland membranes and [(125)I]-hGH from human IM-9 lymphocytes by unlabelled GHs, PRLs or dimeric MER-45-kDa hGH were evaluated. The abilities of dimeric MER-45-kDa hGH to stimulate proliferation of lactogen-responsive Nb2 lymphoma cells and to stimulate proliferation of somatogen-responsive T47-D human breast cancer cells were assessed by incubation of cells with GHs or PRLs and subsequently measuring growth using the MTS cell proliferation assay.
RESULTS: Dimeric MER-45-kDa hGH, compared to monomeric hGH, had reduced binding affinities to both GH and prolactin receptors. In a bovine liver GH radioreceptor assay its ED(50) (197.5 pM) was 40.8% that of monomeric hGH. In a human IM-9 lymphocyte hGH RRA its ED(50) (2.96 nM) was 26.2% that of monomeric hGH. In a lactating rabbit mammary gland prolactin RRA its ED(50) (3.56 nM) was 16.8% that of a monomeric hGH. Dimeric MER-45-kDa hGH, compared to monomeric hGH, had a diminished capacity to stimulate proliferation of cells in vitro. In a dose-response relationship assessing proliferation of Nb2 lymphoma cells its ED(50) (191 pM) was 18.0% that of monomeric hGH. While monomeric hGH stimulated a 2.2-fold proliferation of T47-D human breast cancer cells above vehicle control, dimeric MER-45-kDa hGH was unable to stimulate the cells to proliferate and slightly inhibited their proliferation to 77.6% that of control.
CONCLUSIONS: The topological arrangement of monomeric hGHs to form an unusually stable disulfide-linked dimer markedly diminishes hGH's binding affinities to both GH and PRL receptors and also drastically attenuates its ability to stimulate proliferation of cells in vitro.
Authors:
Juan J Bustamante; Alexei L Grigorian; Jesus Muñoz; Roberto M Aguilar; Lisa R Treviño; Andrew O Martinez; Luis S Haro
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-05-15
Journal Detail:
Title:  Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society     Volume:  20     ISSN:  1532-2238     ISO Abbreviation:  Growth Horm. IGF Res.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-09     Completed Date:  2011-01-20     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  9814320     Medline TA:  Growth Horm IGF Res     Country:  Scotland    
Other Details:
Languages:  eng     Pagination:  298-304     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Cattle
Cell Line, Tumor
Cell Proliferation*
Female
Human Growth Hormone / chemistry*,  genetics,  metabolism*
Humans
Lymphocytes / metabolism
Prolactin / metabolism
Protein Isoforms / genetics,  metabolism
Rabbits
Rats
Receptors, Prolactin / metabolism
Grant Support
ID/Acronym/Agency:
GM08194/GM/NIGMS NIH HHS; GM60655/GM/NIGMS NIH HHS; R25 GM060655/GM/NIGMS NIH HHS; S06 GM008194-230037/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Protein Isoforms; 0/Receptors, Prolactin; 12629-01-5/Human Growth Hormone; 9002-62-4/Prolactin
Comments/Corrections

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