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

Mol Endocrinol. 1991 Nov;5(11):1677-86. doi: 10.1210/mend-5-11-1677.

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 approximately 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 GH-dependent 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Antisense Elements (Genetics)
  • Base Sequence
  • Chromosome Deletion
  • Cloning, Molecular
  • Diabetes Mellitus, Experimental / genetics*
  • Exons*
  • Fasting / physiology*
  • Fetus
  • Gene Expression Regulation*
  • Gene Library
  • Insulin-Like Growth Factor I / genetics*
  • Liver / growth & development
  • Liver / physiology*
  • Liver / physiopathology
  • Male
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides
  • Protein Sorting Signals / genetics*
  • RNA Probes
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / genetics
  • RNA, Messenger / isolation & purification
  • Rats
  • Rats, Inbred Strains
  • Restriction Mapping
  • Transcription, Genetic

Substances

  • Antisense Elements (Genetics)
  • Oligodeoxyribonucleotides
  • Protein Sorting Signals
  • RNA Probes
  • RNA, Messenger
  • Insulin-Like Growth Factor I