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Proinsulin Binds to a Growth Peptide Receptor and Stimulates DNA Synthesis in Chick Embryo Fibroblasts¹

Endocrinology Section, Metabolism Branch, National Cancer Institute and Diabetes Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health Bethesda, Maryland 20014

Abstract

Proinsulin, the biosynthetic precursor of insulin, has 3–5% the potency of insulin in various in vitro assays for insulin-like metabolicactivity. We now report that proinsulin was approximately 60% as potent as insulin and 20% as potent as the growth polypeptide, multiplication stimulating activity (MSA), in stimulating [³H]thymidine incorporation into DNA in chick embryo fibroblasts (CEFs). The stimulation by maximally effective concentrations of proinsulin plus MSA or insulin was not additive. The [³H]thymidine incorporation data reflected DNA synthesis since proinsulin also stimulated DNA synthesis as measured by flow microfluorometry and promoted the multiplication of CEFs. Proinsulin also competed with [¹²⁵I]- iodoMSA for binding to CEFs, and with 60% the potency of insulin. Moreover, MSA binding was inhibited by the same concentrations of proinsulin that were required to stimulate [³H]thymidine incorporation into DNA. The activity of proinsulin in the [³H]thymidine incorporation and MSA radioreceptor assays appeared to be an intrinsic property of the proinsulin molecule, since there was no evidence for conversion of proinsulin to insulin or proinsulin intermediates during incubation. In addition, C-peptide, the peptide bridge connecting the insulin A and B chains in the proinsulin molecule, was inactive in stimulating thymidine incorporation into DNA and in competing with labeled MSA for binding to CEFs.

Footnotes

¹ Presented at the 1976 meeting of the Society of Biological Chemists, San Francisco, Fed Proc 35: 1628, 1976.

Received November 1, 1976.

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