Disease relevance of INSIG2

• We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity [1].
• Gene silencing experiments confirmed that INSIG1, but not INSIG2, regulates the expression of sterol regulatory element-binding proteins target genes in human hepatoma cells [2].

High impact information on INSIG2

• In cultured cells Insig-1 and Insig-2 have been shown to block lipid synthesis in a cholesterol-dependent fashion by inhibiting proteolytic processing of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate lipid synthesis [3].
• In sterol-depleted cells Insig-1 is degraded at least 15 times more rapidly than Insig-2, owing to ubiquitination of Lys-156 and Lys-158 in Insig-1 [4].
• Alanine substitution of the corresponding aspartic acid in Insig-2 produced the same dual defects [5].
• Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis [5].
• Insig-1 and Insig-2 also enhance the conformational change in SCAP that occurs upon addition of certain cationic amphiphiles, such as chlorpromazine, trifluoperazine, and imipramine, which mimic the effect of cholesterol [6].

Biological context of INSIG2

• Here, we use RNA interference to show that sterol-accelerated ubiquitination of reductase requires Insig-1 and Insig-2, membrane-bound proteins of the endoplasmic reticulum that were shown previously to accelerate degradation of reductase when overexpressed by transfection [7].
• INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families [8].
• Recently a large genetic association study showed evidence for association of the single nucleotide polymorphism (SNP) rs7566605, which lies 10 Kb 5' to the first exon of the insulin-induced gene 2 (INSIG-2), with obesity in several cohorts [8].

Anatomical context of INSIG2

• Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins [9].
• Sterol-dependent ubiquitination of reductase in permeabilized cells is dependent upon exogenous cytosol, ATP, and either Insig-1 or Insig-2, two membrane-bound ER proteins shown previously to mediate sterol regulation of reductase degradation in intact cells [10].

Associations of INSIG2 with chemical compounds

• When Glu-214 is changed to alanine, Insig-2 becomes ubiquitinated, but it is still not degraded as rapidly as ubiquitinated Insig-1 [4].

Analytical, diagnostic and therapeutic context of INSIG2

• (Reports, 14 April 2006, p. 279) found that the rs7566605 genetic variant, located upstream of the INSIG2 gene, was consistently associated with increased body mass index [11].

References