INSIG2

4J825114172999ENSG00000125629ENSMUSG00000003721Q9Y5U4Q91WG1NM_001321333NM_001271531NM_001271532NM_133748NM_178082NM_001357251NP_057217NP_001258460NP_001258461NP_598509NP_835183NP_001344180Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene. Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene. Insulin activates the human INSIG2 promoter in a process mediated by phosphorylated SAP1a. Akt mediates suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. MCHR2 has been observed to significantly decrease INSIG2. Insig2 is upregulated under hypoxic conditions and is associated with the malignant potential of pancreatic cancer. A novel 1alpha,25-dihydroxyvitamin D3 response element in the promoter region of Insig-2 gene was identified which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR. The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1. Both INSIG1 protein and this protein are endoplasmic reticulum proteins that block the processing of sterol regulatory element binding proteins (SREBPs) by binding to SREBP cleavage-activating protein (SCAP), and thus prevent SCAP from escorting SREBPs to the Golgi. Insig deficiency in mice caused a marked buildup of cholesterol precursors in skin associated with a marked increase in 3-hydroxy-3-methylglutaryl coenzyme A reductase protein and hair and skin defects corrected by topical simvastatin, an inhibitor of reductase. REV-ERBalpha participates in the circadian modulation of sterol regulatory element-binding protein (SREBP) activity, and thereby in the daily expression of SREBP target genes involved in cholesterol and lipid metabolism. This control is exerted via the cyclic transcription of Insig2, encoding a trans-membrane protein that sequesters SREBP proteins to the endoplasmic reticulum membranes and thereby interferes with the proteolytic activation of SREBPs in Golgi membranes. REV-ERBalpha also participates in the cyclic expression of cholesterol-7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in converting cholesterol to bile acids. Findings suggest that this control acts via the stimulation of LXR nuclear receptors by cyclically produced oxysterols such that rhythmic cholesterol and bile acid metabolism is not just driven by alternating feeding-fasting cycles, but also by REV-ERBalpha, a component of the circadian clockwork circuitry.