INSIG2
Encyclopedia
Insulin induced gene 2, also known as INSIG2, is a protein
which in humans is encoded by the INSIG2 gene
.
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 [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.
. 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
.
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.
Silibinin
inhibits adipocyte differentiation through a potential up-regulation of insig-1 and insig-2 at an early phase in adipocyte differentiation.
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.
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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the INSIG2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Regulation
InsulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
activates the human INSIG2 promoter in a process mediated by phosphorylated SAP1a
SAP1a
SAP1A is one of a family of proteins that contains a unique DNA binding domain termed the ETS domain.-Transcription:The transcriptional activation domain of SAP1a resides within the C-terminal region, the function of which may be impeded by the N-terminus...
.
Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
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 [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.
Function
The protein encoded by this gene is highly similar to the protein product encoded by gene INSIG1INSIG1
Insulin induced gene 1, also known as INSIG1, is a protein which in humans is encoded by the INSIG1 gene.- Function :Oxysterols regulate cholesterol homeostasis through liver X receptor and sterol regulatory element-binding protein mediated signaling pathway. This gene is an insulin-induced gene...
. Both INSIG1 protein and this protein are endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
proteins that block the processing of sterol regulatory element binding proteins (SREBPs
Sterol regulatory element binding protein
Sterol Regulatory Element-Binding Proteins are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors...
) by binding to SREBP cleavage-activating protein (SCAP
SREBP cleavage activating protein
Sterol regulatory element-binding protein cleavage-activating protein, also known as SREBP cleavage-activating protein or SCAP is a protein that in humans is encoded by the SCAP gene....
), and thus prevent SCAP from escorting SREBPs to the Golgi
Golgi alpha-mannosidase II
Golgi α-mannosidase II is a key enzyme involved in N-linked Glycan processing. It is inhibited by small molecule swainsonine....
.
Clinical Significance
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.
Silibinin
Silibinin
Silibinin , also known as silybin, is the major active constituent of silymarin, standardized extract of the milk thistle seeds, containing mixture of flavonolignans consisting of among others of silibinin, isosilibinin, silicristin and silidianin. Silibinin itself is mixture of two diastereomers...
inhibits adipocyte differentiation through a potential up-regulation of insig-1 and insig-2 at an early phase in adipocyte differentiation.
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.
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
Bcl-2-associated X protein
The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
) 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.