Multifactorial regulation of IGF‐I gene expression

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Abstract
Insulin‐like growth factor‐I (IGF‐I) is a highly conserved 70‐residue circulating peptide with diverse biological effects. In mammals IGF‐I is an essential mediator of normal postnatal growth and its expression is influenced by hormonal, nutritional, tissue‐specific, and developmental factors. Recent studies have demonstrated that the IGF‐I gene is more complicated than might have been predicted from its simple protein sequence. In rats and in humans the single‐copy six‐exon gene is transcribed by adjacent promoters into nascent RNAs with different 5′ leader sequences that undergo both alternative RNA splicing and differential polyadenylation to yield multiple mature transcripts. These observations suggest that trophic agents may modulate expression of IGF‐I at any of several nodal points. In this report we review several of the mechanisms responsible for regulating production of IGF‐I in the rat. During neonatal development IGF‐I gene transcription is progressively activated leading to a rise in both hepatic IGF‐I mRNA and in serum IGF‐I. The induction of IGF‐I expression is limited to mRNAs directed by promoter 1, the more 5′ of two rat IGF‐I gene promoters, and precedes the ontogenic appearance of liver growth hormone (GH) receptors, indicating that mechanisms independent of GH activate IGF‐I expression during early postnatal life. By contrast, in adult GH‐deficient rats, a single intraperitoneal injection of GH causes a prompt rise in IGF‐I gene transcription that is mediated equivalently by promoters 1 and 2. Transcriptional induction occurs within 30 min of GH treatment and is associated with a transiently appearing DNase I hypersensitive site in the second IGF‐I intron. These two physiological models show that IGF‐I expression is mediated by at least two distinct transcriptional mechanisms. A challenge for the future will be to define the transcription factors and delineate the critical steps in the regulation of a growth factor that is essential for normal growth and maturation.