This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Byun, D. Articles by Qin, X. Search for Related Content PubMed PubMed Citation Articles by Byun, D. Articles by Qin, X.

Studies on Human Pregnancy-Induced Insulin-Like Growth Factor (IGF)-Binding Protein-4 Proteases in Serum: Determination of IGF-II Dependency and Localization of Cleavage Site¹

J. L. Pettis Veterans Administration Medical Center (D.B., S.M., D.J.B., X.Q.), Loma Linda, California 92357; and the Departments of Endocrinology (C.K., K.S., M.Y.) and Gynecology and Obstetrics (H.L.), Soon Chun Hyang University Hospital, Seoul, Korea

Address all correspondence and requests for reprints to: Dr. Xuezhong Qin, Musculoskeletal Disease Center, J. Pettis Veterans Administration Medical Center (151), 11201 Benton Street, Loma Linda, California 92357. E-mail: Xuezhong.Qin{at}med.va.gov

Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4), a consistent inhibitor of IGF action, is subject to proteolytic cleavage by the IGF-II-dependent IGFBP-4 protease. However, regulation of the IGF-II-dependent IGFBP-4 protease in vivo is not known. As IGFBP proteases are known to be triggered during pregnancy, we systematically evaluated the changes in IGFBP-4 proteolysis by serum collected throughout human pregnancy. Results from in vitro protease assays using recombinant IGFBP-4 revealed that IGFBP-4 proteolysis determined in both the presence and absence of exogenous IGF-II significantly increased during the first and second trimesters and reached a plateau by the third trimester. However, in the absence of IGF-II, IGFBP-4 proteolysis by pregnancy serum was only observed after prolonged incubation. IGF-II dose dependently increased IGFBP-4 proteolysis by pregnancy serum, with maximal stimulation observed at a concentration of 0.7 mol/L relative to IGFBP-4. In contrast, IGF-II at an equimolar dose had little effect on proteolysis of recombinant human IGFBP-3, whereas excess IGF-II reproducibly inhibited recombinant human IGFBP-3 proteolysis by pregnancy serum. Although IGF-II enhanced IGFBP-4 proteolysis, results from N-terminal sequence and mass spectrometric analyses of IGFBP-4 proteolytic fragments demonstrate that the cleavage site (Met¹³⁵-Lys¹³⁶) in human IGFBP-4 was not altered by IGF-II. Deletion of the residues 121–141 containing this cleavage site blocked IGFBP-4 proteolysis. These findings demonstrate that the increase in IGFBP-4 proteolysis during pregnancy was accounted for mainly by the IGF-II-dependent IGFBP-4 proteolysis. Because IGFBP-4 is a potent inhibitor of IGF actions, it can be speculated that the pregnancy-induced IGFBP-4 proteases may play an important role in regulating fetal growth.

This article has been cited by other articles:

				Y. Ning, A. G. P. Schuller, C. A. Conover, and J. E. Pintar Insulin-Like Growth Factor (IGF) Binding Protein-4 Is Both a Positive and Negative Regulator of IGF Activity in Vivo Mol. Endocrinol., May 1, 2008; 22(5): 1213 - 1225. [Abstract] [Full Text] [PDF]

				L. J. Spicer Proteolytic Degradation of Insulin-Like Growth Factor Binding Proteins by Ovarian Follicles: A Control Mechanism for Selection of Dominant Follicles Biol Reprod, May 1, 2004; 70(5): 1223 - 1230. [Abstract] [Full Text] [PDF]

				C. A. Conover, L. K. Bale, M. T. Overgaard, E. W. Johnstone, U. H. Laursen, E.-M. Fuchtbauer, C. Oxvig, and J. van Deursen Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development Development, March 1, 2004; 131(5): 1187 - 1194. [Abstract] [Full Text] [PDF]

				M. Zhang, E. P. Smith, H. Kuroda, W. Banach, S. D. Chernausek, and J. A. Fagin Targeted Expression of a Protease-resistant IGFBP-4 Mutant in Smooth Muscle of Transgenic Mice Results in IGFBP-4 Stabilization and Smooth Muscle Hypotrophy J. Biol. Chem., June 7, 2002; 277(24): 21285 - 21290. [Abstract] [Full Text] [PDF]

				E. P. Smith, A. Kamyar, W. Niu, J. Wang, B. Cercek, S. D. Chernausek, and J. A. Fagin IGF-Binding Protein-4 Expression and IGF-Binding Protein-4 Protease Activity Are Regulated Coordinately in Smooth Muscle During Postnatal Development and After Vascular Injury Endocrinology, October 1, 2001; 142(10): 4420 - 4427. [Abstract] [Full Text] [PDF]

				G.M. Rivera, Y.A. Chandrasekher, A.C.O. Evans, L.C. Giudice, and J.E. Fortune A Potential Role for Insulin-Like Growth Factor Binding Protein-4 Proteolysis in the Establishment of Ovarian Follicular Dominance in Cattle Biol Reprod, July 1, 2001; 65(1): 102 - 111. [Abstract] [Full Text] [PDF]

				D. Byun, S. Mohan, M. Yoo, C. Sexton, D. J. Baylink, and X. Qin Pregnancy-Associated Plasma Protein-A Accounts for the Insulin-Like Growth Factor (IGF)-Binding Protein-4 (IGFBP-4) Proteolytic Activity in Human Pregnancy Serum and Enhances the Mitogenic Activity of IGF by Degrading IGFBP-4 in Vitro J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 847 - 854. [Abstract] [Full Text]

				M. Zygmunt, D.M. Mazzuca, J. Walton, and V.K.M. Han Local fetal signal is not required for maintaining IGFBP gene expression in the human decidua: evidence from extrauterine pregnancies Mol. Hum. Reprod., October 1, 2000; 6(10): 959 - 965. [Abstract] [Full Text] [PDF]

				M. T. Overgaard, J. Haaning, H. B. Boldt, I. M. Olsen, L. S. Laursen, M. Christiansen, G. J. Gleich, L. Sottrup-Jensen, C. A. Conover, and C. Oxvig Expression of Recombinant Human Pregnancy-associated Plasma Protein-A and Identification of the Proform of Eosinophil Major Basic Protein as Its Physiological Inhibitor J. Biol. Chem., September 29, 2000; 275(40): 31128 - 31133. [Abstract] [Full Text] [PDF]