INSIG2

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Insulin induced gene 2
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols INSIG2 ; MGC26273
External IDs OMIM608660 MGI1920249 HomoloGene9400 GeneCards: INSIG2 Gene
RNA expression pattern
PBB GE INSIG2 209566 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 51141 72999
Ensembl ENSG00000125629 ENSMUSG00000003721
UniProt Q9Y5U4 Q91WG1
RefSeq (mRNA) NM_016133 NM_001271531
RefSeq (protein) NP_057217 NP_001258460
Location (UCSC) Chr 2:
118.85 – 118.87 Mb
Chr 1:
121.3 – 121.33 Mb
PubMed search [1] [2]

Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.[1][2]

Regulation[edit]

Insulin activates the human INSIG2 promoter in a process mediated by phosphorylated SAP1a. [3]

Akt mediates suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. [4]

MCHR2 has been observed to significantly decrease INSIG2. [5]

Insig2 is upregulated under hypoxic conditions and is associated with the malignant potential of pancreatic cancer.[6]

A novel 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 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.[7]

Function[edit]

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.[2]

Clinical Significance[edit]

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.[8]

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.[9]

Silibinin inhibits adipocyte differentiation through a potential up-regulation of insig-1 and insig-2 at an early phase in adipocyte differentiation.[10]

The triacylglycerol reducing effect of fibrates and thiazolidinediones, strong and selective agonists of PPARalpha and PPARgamma, is partially caused by inhibition of SREBP-1 activation via up-regulation of Insig.[11]

Findings suggest that Insig2 is a novel colon cancer biomarker. Over-expression of Insig2 appeared to suppress chemotherapeutic drug treatment-induced Bcl2 associated X protein (Bax) expression and activation. Insig2 was also found to localize to the mitochondria/heavy membrane fraction and associate with conformationally changed Bax. Moreover, Insig2 altered the expression of several additional apoptosis genes located in mitochondria.[12] In a study by Kumar et al., the common polymorphisms in INSIG2 gene was not found to be significant in Indian population.[13]

References[edit]

  1. ^ Yabe D, Brown MS, Goldstein JL (October 2002). "Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins". Proceedings of the National Academy of Sciences of the United States of America 99 (20): 12753–8. doi:10.1073/pnas.162488899. PMC 130532. PMID 12242332. 
  2. ^ a b "Entrez Gene: INSIG2 insulin induced gene 2". 
  3. ^ Fernández-Alvarez A, Soledad Alvarez M, Cucarella C, Casado M (April 2010). "Characterization of the human insulin-induced gene 2 (INSIG2) promoter: the role of Ets-binding motifs". J. Biol. Chem. 285 (16): 11765–74. doi:10.1074/jbc.M109.067447. PMC 2852912. PMID 20145255. 
  4. ^ Yecies JL, Zhang HH, Menon S, et al. (July 2011). "Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways". Cell Metab. 14 (1): 21–32. doi:10.1016/j.cmet.2011.06.002. PMID 21723501. 
  5. ^ Zhang Q, Yuan CF, Wu MJ, et al. (June 2010). "Comparative proteomic analysis of proteins influenced by melanin-concentrating hormone and melanin-concentrating hormone receptor 2 interaction". Horm. Metab. Res. 42 (7): 521–7. doi:10.1055/s-0030-1249019. PMID 20340065. 
  6. ^ Tribulová N, Slezák J, Ravingerová T, Ziegelhöffer A (1990). "Transmural non-homogeneity of calcium-induced heart injury". Physiol Bohemoslov 39 (2): 147–50. PMID 2144354. 
  7. ^ Lee S, Lee DK, Choi E, Lee JW (February 2005). "Identification of a functional vitamin D response element in the murine Insig-2 promoter and its potential role in the differentiation of 3T3-L1 preadipocytes". Mol. Endocrinol. 19 (2): 399–408. doi:10.1210/me.2004-0324. PMID 15528275. 
  8. ^ "Hair Growth Defects in Insig-Deficient Mice Caused by Cholesterol Precursor Accumulation and Reversed by Simvastatin". J Invest Dermatol 130 (5). doi:10.1038/jid.2009.442. PMC 2929004. PMID 20090767. 
  9. ^ Le Martelot G, Claudel T, Gatfield D, et al. (September 2009). "REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis". PLoS Biol. 7 (9): e1000181. doi:10.1371/journal.pbio.1000181. PMC 2726950. PMID 19721697. 
  10. ^ Ka SO, Kim KA, Kwon KB, Park JW, Park BH (May 2009). "Silibinin attenuates adipogenesis in 3T3-L1 preadipocytes through a potential upregulation of the insig pathway". Int. J. Mol. Med. 23 (5): 633–7. PMID 19360322. 
  11. ^ König B, Koch A, Spielmann J, et al. (March 2009). "Activation of PPARalpha and PPARgamma reduces triacylglycerol synthesis in rat hepatoma cells by reduction of nuclear SREBP-1". Eur. J. Pharmacol. 605 (1-3): 23–30. doi:10.1016/j.ejphar.2009.01.009. PMID 19248225. 
  12. ^ Li CG, Gruidl M, Eschrich S, et al. (July 2008). "Insig2 is associated with colon tumorigenesis and inhibits Bax-mediated apoptosis". Int. J. Cancer 123 (2): 273–82. doi:10.1002/ijc.23510. PMC 2650850. PMID 18464289. 
  13. ^ Kumar J, Sunkishala RR, Karthikeyan G, Sengupta S.' (May 2007). "In a study by Kumar et al., the common genetic variant upstream of INSIG2 gene is not associated with obesity in Indian population". Clin Genet 71 (5): 415–8. doi:10.1111/j.1399-0004.2007.00795.x. PMID 17489846. 

Further reading[edit]