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Organization and Regulation of the Gene Encoding the Sheep Acid-Labile Subunit of the 150-Kilodalton Insulin-Like Growth Factor-Binding Protein Complex¹

Department of Animal Science, Cornell University (R.P.R., A.W.B., Y.R.B.), Ithaca, New York 14853; and New South Wales Agriculture Beef Industry Center, University of New England P.L.G.), Armidale, New South Wales 2351, Australia

Address all correspondence and requests for reprints to: Dr. Yves R. Boisclair, 259 Morrison Hall, Cornell University, Ithaca, New York 14853-4801. E-mail: yrb1{at}cornell.edu

In adult animals, most circulating insulin-like growth factor I (IGF-I) and IGF-II is sequestered in a 150-kDa complex composed of 1 molecule each of IGF, IGF-binding protein-3 or -5, and the acid-labile subunit (ALS). Capture of IGF in ALS-containing complexes increases their circulating half-lives and concentrations and suppresses their hypoglycemic potential. ALS has been studied almost exclusively in rodents and primates, and no information exists in the sheep despite its extensive use to study the circulating IGF system. To initiate studies in the sheep, we isolated the ovine ALS gene and characterized its spatial and developmental regulation. The ALS gene spans about 3.0 kb of chromosomal DNA and consists of 2 exons interrupted by a 977-bp intron. Exon 1 encodes the first 5 amino acids of the signal peptide; exon 2 encodes the remaining 27 amino acids of the signal peptide and the entire mature protein of 579 amino acids. Transcription initiation occurs at nucleotides -58 and -29 (ATG, +1), 2 sites that are not preceded by TATA or initiator sequences. A DNA fragment extending from -727 to -11 of the sheep ALS gene directed basal expression of a luciferase reporter plasmid in the rat liver cell line H4-II-E. GH increased promoter activity by 1.8-fold, consistent with conservation in the sheep promoter of the GH response element previously identified in the mouse gene. A survey of adult tissues by Northern analysis revealed the presence of a 2.2-kb transcript only in liver. Weak expression was first detected in liver on day 130 of fetal life, increased suddenly on day 7 of postnatal age, and changed little thereafter. The sheep is a useful model to understand the regulation and role of ALS, particularly around the time of birth, when final maturation of the circulating IGF system occurs.

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