The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

Abstract

The insulinlike growth factor-I (IGF-I) is an important factor which regulates a variety of cellular responses in multiple biological systems. The IGF1 gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing. These multiple transcripts code for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms in humans, which also undergo posttranslational modifications, such as proteolytic processing and glycosylation. IGF-I actions are mediated through its binding to several cell-membrane receptors and the IGF-I domain responsible for the receptor binding is the bioactive mature IGF-I peptide, which is derived after the posttranslational cleavage of the pro-IGF-I isoforms and the removal of their carboxy-terminal E-peptides (that is, the Ea, Eb and Ec). Interestingly, differential biological activities have been reported for the different IGF-I isoforms, or for their E-peptides, implying that IGF-I peptides other than the IGF-I ligand also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects. The multiple peptides derived from IGF-I and the differential expression of its various transcripts in different conditions and pathologies appear to be compatible with the distinct cellular responses observed to the different IGF-I peptides and with the concept of a complex and possibly isoform-specific IGF-I bioactivity. This concept is discussed in the present review, in the context of the broad range of modifications that this growth factor undergoes which might regulate its mechanism(s) of action.

Effect of hypoxia on the expression of genes encoding insulin-like growth factors and some related proteins in U87 glioma cells without IRE1 function

“…Furthermore, formation of hybrid receptor isoforms between receptors for IGF1 and insulin as well as hybrid receptors of IGF1/INS receptor with other tyrosine kinase potentiate the transformation of cells, tumorigenesis, and tumor neovascularization (Weroha and Haluska 2012; Dai et al 2013;Baxter 2014;Singh et al 2014;Zhu et al 2014). Moreover, insulin system including ligands (insulin and IGFs) and their shared receptors (INS/IGF receptors) are critical regulators of insulin signaling and glucose homeostasis (Philippou et al 2014;Singh et al 2014).…”

“…Th e expression of IGFs, their receptors, and binding proteins are regulated at transcription and posttranscriptional levels (Panda et al 2013). Moreover, the eff ect of IGF1 in the regulation of tumor cell growth depends on its mRNA splicing and posttranslational modifi cations, such as proteolytic processing and glycosylation (Philippou et al 2014;Halje et al 2012). Recently, it has been shown that a long non-coding RNA responsive to IGF/INS signaling (CRNDE) regulates genes involved in central metabolism processes (Ellis et al 2014) and that platelet-released miR-223 promotes advanced glycation end product-induced vascular endothelial cell apoptosis via targeting insulin-like growth factor 1 receptor (Pan et al 2014).…”

Optimizing Mechanical Stretching Protocols for Hypertrophic and Anti-apoptotic Responses in H9c2 Cardiomyocytes

“…Mechanical loading of skeletal and cardiac muscle cells both in vivo and in vitro can lead to the upregulation of many growth factors, including IGF-1, and the activation of signaling pathways associated with protein synthesis and cell growth, eventually leading to muscle hypertrophy [10, 24-26, 38, 39]. Indeed, IGF-1 upregulation and signaling have been implicated in the mechanical loading-induced adaptive cardiac hypertrophy [10,25,26], while potentially differential actions of IGF-1 isoforms in myocardial repair/remodeling process have been proposed [27][28][29]40]. To the authors' best knowledge, this is the rst study investigating the distinct expression pro les of IGF-1 isoforms following mechanical loading of cardiac myotubes, in vitro.…”

The growth endocrine axis and inflammatory responses after laparoscopic cholecystectomy

“…14 Many GH actions are mediated by insulin-like growth factor-1 (IGF-1), which, in the context of its endocrine activity, is produced and secreted by the liver, skeletal muscle, and other tissues in response to stimulation by GH. [19][20][21] Furthermore, it has been proposed that acute inflammation induces a GH-resistant state as part of a regulatory mechanism of the body to restrict growth and energy storage, in which the elevated GH secretion is not followed by increased circulating IGF-1 levels. [22][23][24] Although the effect of surgical stress and/or inflammatory responses on endocrine function after laparoscopic surgery has been described in humans, 2,13,[25][26][27] studies designed to detect the relation between the response of the anabolic GH/IGF-1 axis and laparoscopic cholecystectomy in the context of an acute phase response are lacking.…”