Regulation of start site usage in the leader exons of the rat insulin-like growth factor-I gene by development, fasting, and diabetes

Martin L. Adamo, Haya Ben-Hur, Charles T. Roberts, Derek LeRoith

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

Rat insulin-like growth factor-I (IGF-I) mRNAs with different 5′-untranslated region/prepeptide coding sequences result from transcription initiation in one of two leader exons. While not altering the mature IGF-I coding sequence, these different leaders potentially encode two distinct IGF-I prepeptides, one of 48 amino acids (exon 1) and one of 32 amino acids (exon 2). Within exon 1, transcription initiation is dispersed (i.e. occurs over a ∼350-basepair region), while within exon 2, it is highly localized. A fourth exon 1 start site, residing only approximately 30 basepairs from its 3′ end, is suggested on the basis of RNase protection assays; its use would produce an mRNA encoding a third distinct IGF-I leader peptide of 22 amino acids. We have determined that during postnatal development, and as a result of insulinopenic diabetes and fasting, choice of transcription start sites within exon 1 in the liver is coordinately regulated, i.e. use of all start sites increased during development and decreased in the two catabolic states. Transcription initiation at the single major site within exon 2 was also reduced in diabetes and fasting. Insulin replacement therapy and refeeding restored the levels of all transcripts coordinately. During postnatal development, however, transcripts initiating within exon 2 exhibited a different developmental profile than did exon 1 transcripts, increasing especially at the onset of GHdependent linear growth. In liver, therefore, negative regulation of exon 1 and exon 2 transcription start site usage occurs in catabolic states, while in development, differential regulation of exon 1 and exon 2 transcription start sites occurs.

Original languageEnglish (US)
Pages (from-to)1677-1686
Number of pages10
JournalMolecular Endocrinology
Volume5
Issue number11
DOIs
StatePublished - Nov 1991
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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