Endocrinology, Vol 128, 2693-2701, Copyright © 1991 by Endocrine Society

ARTICLES

Multihormonal regulation of insulin-like growth factor-binding protein- 1 in rat H4IIE hepatoma cells: the dominant role of insulin

TG Unterman, DT Oehler, LJ Murphy and RG Lacson
Department of Medicine, University of Illinois College of Medicine, Chicago.

Circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) and the abundance of hepatic IGFBP-1 mRNA are increased in streptozotocin-diabetic rats and are regulated in accordance with insulin and metabolic status. We recently purified rat IGFBP-1 from medium conditioned by well differentiated rat H4IIE hepatoma cells. Since this cell line provides a useful model for examining the effects of hormones on hepatocellular function, we used H4IIE cells to examine the relative role that insulin and other factors may play in the regulation of IGFBP-1 production. H4IIE cells were stabilized in serum- free medium, then treated with specific hormones. The availability of IGFBPs in conditioned medium was estimated by [125I]IGF-I binding assay, and specific BPs were assessed by Western ligand and immunoblot analyses. The abundance of IGFBP-1 mRNA was determined by Northern and slot blot analysis. Initial studies revealed that [125I]IGF-I-binding activity in conditioned medium was reduced after 24-h incubation with 100 nM insulin (52 +/- 4% of control; P less than 0.001). In contrast, binding activity was increased after only 4 h of incubation with 75 microM 8-(4-chlorophenylthio)cAMP (8-CPT-cAMP) or 1 microM dexamethasone (P less than 0.001 vs. control for each), but these effects were prevented by insulin. Ligand and immunoblotting demonstrated that insulin decreased the production of 32K and 34K forms of IGFBP-1, while both 8-CPT-cAMP and dexamethasone increased the production of IGFBP-1; again, insulin prevented the effects of 8-CPT- cAMP and dexamethasone. Of note, 1 microM rat GH, testosterone, progesterone, or 17 beta-estradiol had no effect on either IGF-binding activity or IGFBP-1 production. Northern and slot blot analyses revealed that 100 nM insulin profoundly lowered the abundance of IGFBP- 1 mRNA in H4IIE cells (4 +/- 0.6% of control at 4 h; P less than 0.001), while IGFBP-1 mRNA was increased 2-fold during incubation with 75 microM 8-CPT-cAMP (P less than 0.001) and 9-fold with 1 microM dexamethasone (P less than 0.001). Once again, the effect of insulin was dominant; insulin both prevented and reversed the effects of maximally effective concentrations of 8-CPT-cAMP and dexamethasone. To determine whether this effect of insulin reflected altered generation or stability of IGFBP-1 mRNA, H4IIE cells were incubated with 2.5 micrograms/ml actinomycin-D with or without insulin, and mRNA was quantitated by Northern blot.(ABSTRACT TRUNCATED AT 400 WORDS)

This article has been cited by other articles:

				G. SCHWEIZER-GROYER, G. FALLOT, F. CADEPOND, C. GIRARD, and A. GROYER The cAMP-Responsive Unit of the Human Insulin-Like Growth Factor-Binding Protein-1 Coinstitutes a Functional Insulin-Response Element Ann. N.Y. Acad. Sci., December 1, 2006; 1091(1): 296 - 309. [Abstract] [Full Text] [PDF]

				A L Pierce, M Shimizu, L Felli, P Swanson, and W W Dickhoff Metabolic hormones regulate insulin-like growth factor binding protein-1 mRNA levels in primary cultured salmon hepatocytes; lack of inhibition by insulin. J. Endocrinol., November 1, 2006; 191(2): 379 - 386. [Abstract] [Full Text] [PDF]

				D. Finlay, A. J Ruiz-Alcaraz, C. Lipina, S. Perrier, and C. Sutherland A temporal switch in the insulin-signalling pathway that regulates hepatic IGF-binding protein-1 gene expression. J. Mol. Endocrinol., October 1, 2006; 37(2): 227 - 237. [Abstract] [Full Text] [PDF]

				M. Shimizu, B. R Beckman, A. Hara, and W. W Dickhoff Measurement of circulating salmon IGF binding protein-1: assay development, response to feeding ration and temperature, and relation to growth parameters J. Endocrinol., January 1, 2006; 188(1): 101 - 110. [Abstract] [Full Text] [PDF]

				J.-G. Scharf, T. G. Unterman, and T. Kietzmann Oxygen-Dependent Modulation of Insulin-Like Growth Factor Binding Protein Biosynthesis in Primary Cultures of Rat Hepatocytes Endocrinology, December 1, 2005; 146(12): 5433 - 5443. [Abstract] [Full Text] [PDF]

				L. Gan, H. Pan, and T. G. Unterman Insulin Response Sequence-Dependent and -Independent Mechanisms Mediate Effects of Insulin on Glucocorticoid-Stimulated Insulin-Like Growth Factor Binding Protein-1 Promoter Activity Endocrinology, October 1, 2005; 146(10): 4274 - 4280. [Abstract] [Full Text] [PDF]

				V. Roelfsema, A. J. Gunn, B. H. Breier, J. S. Quaedackers, and L. Bennet The Effect of Mild Hypothermia on Insulin-like Growth Factors After Severe Asphyxia in the Preterm Fetal Sheep Reproductive Sciences, May 1, 2005; 12(4): 232 - 237. [Abstract] [PDF]

				M Shimizu, J T Dickey, H Fukada, and W W Dickhoff Salmon serum 22 kDa insulin-like growth factor-binding protein (IGFBP) is IGFBP-1 J. Endocrinol., January 1, 2005; 184(1): 267 - 276. [Abstract] [Full Text] [PDF]

				K. T. Coschigano, A. N. Holland, M. E. Riders, E. O. List, A. Flyvbjerg, and J. J. Kopchick Deletion, But Not Antagonism, of the Mouse Growth Hormone Receptor Results in Severely Decreased Body Weights, Insulin, and Insulin-Like Growth Factor I Levels and Increased Life Span Endocrinology, September 1, 2003; 144(9): 3799 - 3810. [Abstract] [Full Text] [PDF]

				C. H. Lang, T. C. Vary, and R. A. Frost Acute in Vivo Elevation of Insulin-Like Growth Factor (IGF) Binding Protein-1 Decreases Plasma Free IGF-I and Muscle Protein Synthesis Endocrinology, September 1, 2003; 144(9): 3922 - 3933. [Abstract] [Full Text] [PDF]

				T. K. Hansen, J. O. L. Jorgensen, and J. S. Christiansen Body Composition and Circulating Levels of Insulin, Insulin-Like Growth Factor-Binding Protein-1 and Growth Hormone (GH)-Binding Protein Affect the Pharmacokinetics of GH in Adults Independently of Age J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2185 - 2193. [Abstract] [Full Text] [PDF]

				J L Chicharro, A Lopez-Calderon, J Hoyos, A I Martin-Velasco, G Villa, M A Villanua, and A Lucia Effects of an endurance cycling competition on resting serum insulin-like growth factor I (IGF-I) and its binding proteins IGFBP-1 and IGFBP-3 Br. J. Sports Med., October 1, 2001; 35(5): 303 - 307. [Abstract] [Full Text] [PDF]

				J. Sugawara, S. I. Tazuke, L. F-Suen, D. R. Powell, F. Kaper, A. J. Giaccia, and L. C. Giudice Regulation of Insulin-Like Growth Factor-Binding Protein 1 by Hypoxia and 3',5'-Cyclic Adenosine Monophosphate Is Additive in HepG2 Cells J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3821 - 3827. [Abstract] [Full Text]

				S. Guo, G. Rena, S. Cichy, X. He, P. Cohen, and T. Unterman Phosphorylation of Serine 256 by Protein Kinase B Disrupts Transactivation by FKHR and Mediates Effects of Insulin on Insulin-like Growth Factor-binding Protein-1 Promoter Activity through a Conserved Insulin Response Sequence J. Biol. Chem., June 11, 1999; 274(24): 17184 - 17192. [Abstract] [Full Text] [PDF]

				P. Menuelle, S. Babajko, and C. Plas Insulin-Like Growth Factor (IGF) Binding Proteins Modulate the Glucocorticoid-Dependent Biological Effects of IGF-II in Cultured Fetal Rat Hepatocytes Endocrinology, May 1, 1999; 140(5): 2232 - 2240. [Abstract] [Full Text]

				G. Schweizer-Groyer, N. Jibard, E. Neau, D. Fortin, F. Cadepond, E.-E. Baulieu, and A. Groyer The Glucocorticoid Response Element II Is Functionally Homologous in Rat and Human Insulin-like Growth Factor-binding Protein-1 Promoters J. Biol. Chem., April 23, 1999; 274(17): 11679 - 11686. [Abstract] [Full Text] [PDF]

				L. P. Koziris, R. C. Hickson, R. T. Chatterton Jr., R. T. Groseth, J. M. Christie, D. G. Goldflies, and T. G. Unterman Serum levels of total and free IGF-I and IGFBP-3 are increased and maintained in long-term training J Appl Physiol, April 1, 1999; 86(4): 1436 - 1442. [Abstract] [Full Text] [PDF]

				C. H. Lang, G. J. Nystrom, and R. A. Frost Regulation of IGF binding protein-1 in Hep G2 cells by cytokines and reactive oxygen species Am J Physiol Gastrointest Liver Physiol, March 1, 1999; 276(3): G719 - G727. [Abstract] [Full Text] [PDF]

				L. E. Levitt Katz, M. S. Satin-Smith, P. Collett-Solberg, L. Baker, C. A. Stanley, and P. Cohen Dual Regulation of Insulin-Like Growth Factor Binding Protein-1 Levels by Insulin and Cortisol during Fasting J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4426 - 4430. [Abstract] [Full Text]

				S. B. Cichy, S. Uddin, A. Danilkovich, S. Guo, A. Klippel, and T. G. Unterman Protein Kinase B/Akt Mediates Effects of Insulin on Hepatic Insulin-like Growth Factor-binding Protein-1 Gene Expression through a Conserved Insulin Response Sequence J. Biol. Chem., March 13, 1998; 273(11): 6482 - 6487. [Abstract] [Full Text] [PDF]

				C. A. Benbassat, K. C. Maki, and T. G. Unterman Circulating Levels of Insulin-Like Growth Factor (IGF) Binding Protein-1 and -3 in Aging Men: Relationships to Insulin, Glucose, IGF, and Dehydroepiandrosterone Sulfate Levels and Anthropometric Measures J. Clin. Endocrinol. Metab., May 1, 1997; 82(5): 1484 - 1491. [Abstract] [Full Text] [PDF]

				B. Gil, M. A. Pajares, J. M. Mato, and L. Alvarez Glucocorticoid Regulation of Hepatic S-Adenosylmethionine Synthetase Gene Expression Endocrinology, March 1, 1997; 138(3): 1251 - 1258. [Abstract] [Full Text] [PDF]

				B. C. Villafuerte, W. Zhao, A. C. Herington, R. Saffery, and L. S. Phillips Identification of an Insulin-responsive Element in the Rat Insulin-like Growth Factor-binding Protein-3 Gene J. Biol. Chem., February 21, 1997; 272(8): 5024 - 5030. [Abstract] [Full Text] [PDF]

				C. J. Band and B. I. Posner Phosphatidylinositol 3'-Kinase and p70s6k Are Required for Insulin but Not Bisperoxovanadium 1,10-Phenanthroline (bpV(phen)) Inhibition of Insulin-like Growth Factor Binding Protein Gene Expression. EVIDENCE FOR MEK-INDEPENDENT ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE BY bpV(phen) J. Biol. Chem., January 3, 1997; 272(1): 138 - 145. [Abstract] [Full Text] [PDF]

				D. Yeagley, S. Guo, T. Unterman, and P. G. Quinn Gene- and Activation-specific Mechanisms for Insulin Inhibition of Basal and Glucocorticoid-induced Insulin-like Growth Factor Binding Protein-1 and Phosphoenolpyruvate Carboxykinase Transcription. ROLES OF FORKHEAD AND INSULIN RESPONSE SEQUENCES J. Biol. Chem., August 31, 2001; 276(36): 33705 - 33710. [Abstract] [Full Text] [PDF]