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Insulin-Like Growth Factor-I (IGF-I) Attenuation of Growth Hormone Is Enhanced by Overexpression of Pituitary IGF-I Receptors

Department of Medicine, Cedars-Sinai Medical Center-University of California Los Angeles, School of Medicine Los Angeles, California 90048

Address requests for reprints to: Shlomo Melmed, M.D., Endocrinology B-131, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048.

Abstract

Insulin-like growth factor-I (IGF-I) attenuates GH gene expression by a receptor-mediated mechanism in pituitary cells. We, therefore, isolated neomycin-resistant stable GC cell transfectants overexpressing human IGF-I receptor cDNA (IGFIRcDNA) cloned in an Rous sarcoma virus-directed expression vector. A transfection control contained the IGFIR-cDNA cloned in the reverse orientation. Southern analysis confirmed incorporation of human IGFIR-cDNA sequences into rat genomic DNA. Immunoprecipitation of metabolically labeled [³⁵S]methionine stably transfected cells revealed a 200-kDa human IGF-I receptor precusor protein. Growth rate and basal GH secretion were not altered in transfected cells. Although transfected and control cells had a similar K_dfor IGF-I binding (0.43 and 0.40 nM, respectively), IGF-l-binding sites were induced 17-fold (384,000 vs. 22,000 sites/cell). Treatment of cells with IGF-I (6.5 nM) maximally attenuated GH secretion by 80% compared to 40% attenuation in control cells (P < 0.0001). Maximal suppression of GH in transfectants occurred within 15 h of treatment, and GH secretion by control cells was only maximally suppressed after 42 h. The ED₅₀ of IGF-I suppression of GH secretion in transfectants after 15 h was 0.5 nM. These results demonstrate that transfectants overexpressing human IGF-I receptor are hyperresponsive to exogenous IGF-I. These data indicate that IGF-I receptor number plays an important role in mediating the signal transduction of IGFI to the GH gene.

FOOTNOTES

This work was supported by NIH Grant DK-34824.

Received for publication March 14, 1991. Revision received April 22, 1991. Accepted for publication April 23, 1991.

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