Document Detail

Studies on regulation of IGF (insulin-like growth factor)-binding protein (IGFBP) 4 proteolysis by pregnancy-associated plasma protein-A (PAPP-A) in cells treated with phorbol ester.
MedLine Citation:
PMID:  14705967     Owner:  NLM     Status:  MEDLINE    
PAPP-A (pregnancy-associated plasma protein-A) is produced by hSFs (human skin fibroblasts) and hOBs (human osteoblasts) and enhances the mitogenic activity of IGFs (insulin-like growth factors) by degradation of IGFBP-4 (insulin-like growth factor-binding protein 4). PKC (protein kinase C) activation in these cells led to reduction in IGFBP-4 proteolysis. This study was undertaken to determine the mechanism by which activation of PKC suppresses IGFBP-4 proteolysis. Treatment of hSFs/hOBs with TPA (PMA; 100 nM) reduced IGFBP-4 proteolysis without significantly decreasing the PAPP-A level in the CM (conditioned medium). Immunodepletion of the proform of eosinophil major basic protein (proMBP), a known PAPP-A inhibitor, from CM of TPA-treated cells (TPA CM) failed to increase IGFBP-4 proteolytic activity. Transduction of hSFs with proMBP retrovirus increased the concentration of proMBP up to 30 ng/ml and led to a moderate reduction in IGFBP-4 proteolysis. In contrast, TPA treatment blocked IGFBP-4 proteolysis but failed to induce a detectable amount of proMBP in the CM. While proMBP overexpression led to the formation of a covalent proMBP-PAPP-A complex and reduced the migration of PAPP-A on SDS/PAGE, TPA treatment dose- and time-dependently increased the conversion of a approximately 470 kDa PAPP-A form (PAPP-A470) to a approximately 400 kDa PAPP-A form (PAPP-A400). Since unreduced PAPP-A400 co-migrated with the 400 kDa recombinant PAPP-A homodimer and since PAPP-A monomers from reduced PAPP-A470 and PAPP-A400 co-migrated on SDS/PAGE, conversion of PAPP-A470 to PAPP-A400 is unlikely to be caused by proteolytic cleavage of PAPP-A. Consistent with the data showing that the increase in the ratio of PAPP-A400/PAPP-A470 is correlated with the extent of reduction in IGFBP-4 proteolysis, partially purified PAPP-A400 exhibited a 4-fold reduction in IGFBP-4 proteolytic activity compared with PAPP-A470. These data suggest that a novel mechanism, namely conversion of PAPP-A470 to the less-active PAPP-A400, could account for the TPA-induced suppression of PAPP-A activity.
Arun S Sivanandam; Subburaman Mohan; Hirohito Kita; Sanjay Kapur; Shin-Tai Chen; Thomas A Linkhart; Gyorgy Bagi; David J Baylink; Xuezhong Qin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Biochemical journal     Volume:  379     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2004 Apr 
Date Detail:
Created Date:  2004-03-22     Completed Date:  2004-07-16     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  57-64     Citation Subset:  IM    
Musculoskeletal Disease Center, J. L. Pettis Memorial Veterans' Medical Center, 11201 Benton Street, Loma Linda, CA 92357, USA.
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MeSH Terms
Antibodies, Monoclonal / pharmacology
Blood Proteins / immunology,  metabolism
Cells, Cultured / drug effects,  metabolism
Culture Media, Conditioned / pharmacology
Enzyme Activation
Eosinophil Granule Proteins
Fibroblasts / drug effects,  metabolism*
Insulin-Like Growth Factor Binding Protein 4 / metabolism*
Molecular Weight
Osteoblasts / drug effects,  metabolism*
Phorbol Esters / pharmacology
Pregnancy-Associated Plasma Protein-A / antagonists & inhibitors,  chemistry,  metabolism*,  physiology*
Protein Isoforms / chemistry,  physiology
Protein Kinase C / metabolism*
Protein Precursors / immunology,  metabolism
Recombinant Fusion Proteins / physiology
Ribonucleases / immunology,  metabolism
Tetradecanoylphorbol Acetate / pharmacology
Transduction, Genetic
Grant Support
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Blood Proteins; 0/Culture Media, Conditioned; 0/Eosinophil Granule Proteins; 0/Insulin-Like Growth Factor Binding Protein 4; 0/Phorbol Esters; 0/Protein Isoforms; 0/Protein Precursors; 0/Recombinant Fusion Proteins; 16561-29-8/Tetradecanoylphorbol Acetate; 24928-17-4/phorbol-12,13-didecanoate; EC Kinase C; EC 3.1.-/Ribonucleases; EC 3.4.24.-/Pregnancy-Associated Plasma Protein-A

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