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Identification, Characterization, and Regulation of a Rat Complementary Deoxyribonucleic Acid which Encodes Insulin-Like Growth Factor-I^*

LIAM J. MURPHY, GRAEME I. BELL, MARY LYNN DUCKWORTH and HENRY G. FRIESEN

Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg R3E 0W1 Canada, and Chiron Corporation (G.I.B.) Emeryville, California 94608

Address correspondence and requests for reprints to: Liam J. Murphy, M.D., Ph.D., Department of Physiology, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3, Canada.

Abstract

A complementary DNA (cDNA) encoding rat insulin-like growth factor 1 (IGF-I) has been isolated from a kidney cDNA library. By analogy with the sequence of human and mouse preproIGF-IA this cDNA encodes rat preproIGF-I from amino acid minus 3 to amino acid 105. The predicted protein sequence shows 96% and 99% homology with the human and mouse preproIGF-I, respectively. Under stringent conditions the rat IGF-I cDNA hybridizes with at least three mRNA, messenger RNA species which have apparent sizes of 7,1.8, and 0.7–1.1 kilobases. All three IGF-I transcripts are detectable in each of the normal rat tissues examined and the relative order of abundance in tissues from intact adult male rats is liver > lung > kidney > thymus > spleen > heart > skeletal muscle (quadriceps femoris) > testes > brain. The GH dependence of the IGF-I mRNAs was demonstrated by the administration of a single ip injection of human GH (hGH) to hypophysectomized (hypox) rats which resulted in an increase in all three transcripts in each of the tissues examined. The increase in IGF-1 mRNAs was most marked in skeletal and cardiac muscle (9.7- and 9.5- fold compared to hypox controls, respectively) and least marked in the brain. In the liver only a 4-fold increase in IGF-I expression was observed, possibly because of the relatively high level of IGF-I expression in the tissue in the hypox control rats. Each of the IGF-I messenger RNAs appeared to increase in parallel and the time course of IGF-I induction was similar in each tissue with maximal levels of IGF-I transcripts present 6 to 12 h after GH administration. A dose-dependent increase in IGF-I mRNAs was observed in most tissues of hypox rats treated for 10 days with hGH. Significant correlations between growth, as determined by body weight gain and IGF-I expression were observed in liver (r=0.97), kidney (r=0.90), quadriceps femoris (r=0.95), diaphragm (r=0.92), and thymus (r=1.0). The IGF-I mRNA levels in tissues from rats that had been treated with the highest dose of hGH (90 µg/ratday) were similar to those observed in normal intact rats. This study confirms the highly conserved nature of the IGF-I precursor and provides clear evidence for the GH dependence of IGF-I gene expression in multiple tissues of the rat. (Endocrinobgy 121: 684–691,1987)

Footnotes

^* This work was supported by MRC Canada, National Cancer Institute of Canada, and USPHS Grant HD-07843-13.

Recipient of a C. J. Martin Travelling Fellowship from the NHMRC of Australia.

Received October 21, 1986.

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