Transcriptional Regulation of INSR, the Insulin Receptor Gene

Abstract

The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development. The insulin signaling pathway plays key roles in processes such as metabolic regulation, growth control, and neuronal function. Misregulation of the pathway features in diabetes, cancer, and neurodegenerative diseases, making it an important target for clinical interventions. While much attention has been focused on differential pathway activation through ligand availability, sensitization of overall signaling may also be mediated by differential expression of the insulin receptor itself. Although first characterized as a “housekeeping” gene with stable expression, comparative studies have shown that expression levels of the human INSR mRNA differ by tissue and in response to environmental signals. Our recent analysis of the transcriptional controls affecting expression of the Drosophila insulin receptor gene indicates that a remarkable amount of DNA is dedicated to encoding sophisticated feedback and feed forward signals. The human INSR gene is likely to contain a similar level of transcriptional complexity; here, we summarize over three decades of molecular biology and genetic research that points to a still incompletely understood regulatory control system. Further elucidation of transcriptional controls of INSR will provide the basis for understanding human genetic variation that underlies population-level physiological differences and disease.

Different response of embryos originating from control and obese mice to insulin <i>in vitro</i>

“…previous study, respectively); the compensatory mechanism could be more advanced (and therefore detectable) than in earlier ones. As shown in various studies on overweight individuals who differed in insulin sensitivity, the expression of insulin receptor is dynamic and varies depending on time [ 49 ].…”

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

“…Several kinases consistently identified as differentially active across multiple pipelines, cell lines, or final combinatorial analyses recapitulate kinases previously identified as playing well-established roles in a variety of human cancer pathologies. These kinases include insulin receptor (INSR) kinase [ 37 , 38 ] ( Figure 2 and Figure 3 , Table 3 and Table 4 ), EPHA2 kinase [ 29 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] ( Figure 2 and Figure 3 , Table 4 ), platelet-derived growth factor receptor alpha (PDGFRA) kinase [ 47 , 48 , 49 , 50 , 51 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), SRC kinase [ 26 , 27 , 52 , 53 , 54 , 55 , 56 , 57 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), and tyrosine kinase nonreceptor 2 (TNK2) kinase [ 58 , 59 , 60 , 61 , 62 , 63 , 64 ...…”

Fenugreek Stimulates the Expression of Genes Involved in Milk Synthesis and Milk Flow through Modulation of Insulin/GH/IGF-1 Axis and Oxytocin Secretion

“…These receptors act through similar pathway mainly by activating the AKT/mTOR pathway [ 56 ]. In addition, insulin stimulates expression of GH receptor in peripheral tissues [ 58 ] but also modulates the expression of IGF1R and INSR [ 59 , 60 ].…”

“…This is consistent with the hypoglycemic effect of fenugreek and its capacity to stimulate insulin secretion through the potential action of trigonelline and 4-hydroxyisoleucin [ 23 , 24 ]. Together with a potential direct action of fenugreek compounds [ 24 ], the rise in plasma insulin under lactation-specific conditions, i.e., hypo-insulinemia and insulin-resistance in peripheral tissues except mammary gland, could explain the Igf1r , Insr and Ghr overexpression in the mammary gland [ 58 , 60 , 61 ]. The increase of IGF-1 and insulin binding to their receptor and to their hybrid receptor leads to an activation of the AKT/mTOR pathway, as suggested by overexpression of Mtor at L12 (by 1.84-fold) and of Akt1 to a lesser extent ( Table 4 ) and results in activation of lactose and protein synthesis [ 19 ].…”