Regulation of gene expression by insulin

O’Brien, Richard M.; Granner, Daryl K.

doi:10.1042/bj2780609

Cited by 271 publications

(112 citation statements)

References 181 publications

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“…This stimulation does not depend on extracellular glucose [20,21] and occurs within 30 min [22]. No insulin response element (IRE) has been experimentally localized on the liver promoter, but O'Brien and Granner [23] pointed to the existence of a TGGTTCTTTG motif at -83 that resembles the negative insulin response sequence (IRS) TGGTGTTTTG of the PEPCK gene. Glucagon, acting via cyclic AMP, inhibits the stimulation by insulin [20].…”

Section: Gene Organizationmentioning

confidence: 99%

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

Lemaigre¹,

Rousseau²

1994

Biochemical Journal

100

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Section: Gene Organizationmentioning

confidence: 99%

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

Lemaigre¹,

Rousseau²

1994

Biochemical Journal

100

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“…The synergistic effect of DEX is also apparent in the absence of co-transfected Stat5 expression vectors. Therefore, a significant fraction of the endogenous Stat5 proteins are likely to be interacting with the GR, and this may be important for genes that are synergistically regulated by insulin and glucocorticoids, such as glucokinase (32). Although the Stat5-GR interaction may lead to significant increases in the activation of Stat5 target genes, this interaction has also been shown to lead to a decreased ability of the GR to transactivate a simple GRE-containing reporter gene (28).…”

Section: Fig 3 a Lower Ratio Of Irs-1 And/or -2 To Ir Correlates Wimentioning

confidence: 99%

Insulin Induction of SOCS-2 and SOCS-3 mRNA Expression in C2C12 Skeletal Muscle Cells Is Mediated by Stat5*

Sadowski¹,

Choi

Le³

et al. 2001

Journal of Biological Chemistry

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Previously, by a yeast 2-hybrid screen, we identified signal transducer and activator of transcription 5b (Stat5b) as a substrate of the insulin receptor (IR). We demonstrated that refeeding of fasted mice leads to rapid activation of Stat5 proteins in liver, skeletal muscle, and fat, suggesting that Stat5b is a physiological target of insulin. Here, we show that injection of glucose or insulin into fasted mice leads to robust activation of both Stat5a and Stat5b in skeletal muscle. In C2C12 myotubes, we find that insulin stimulates tyrosine phosphorylation of Stat5a and Stat5b by 3-5-fold. This degree of Stat5 activation in vitro is significantly lower than what we observe in vivo and inversely correlates with IRS-1/2 levels. We can recapitulate robust insulin activation of Stat5 in C2C12 cells by stable overexpression of the human IR (hIR). To identify insulin-activated genes that are Stat5 targets, we also overexpressed an IR mutant (LA-hIR) that signals normally for mitogenactivated protein kinase-and phosphatidylinositol 3-kinase-dependent pathways but is deficient in Stat5 signaling in response to insulin. We demonstrate that insulin induces the expression of SOCS-2 mRNA in the wild type hIR but not in the LA-hIR-overexpressing cells. The induction of SOCS-3 by insulin is reduced but not lost in the LA-hIR cells. Therefore, our results suggest that insulin induction of SOCS-2, and in part SOCS-3 mRNA expression, is mediated by Stat5 and can be independent of mitogen-activated protein kinase and phosphatidylinositol 3-kinase-signaling pathways.Insulin plays a pivotal role in the regulation of glucose homeostasis and exerts numerous metabolic and proliferative responses in insulin-sensitive tissues (1). These effects are mediated by the binding of insulin and subsequent activation of the insulin receptor (IR) 1 tyrosine kinase (1). The activated receptor phosphorylates itself as well as several other intracellular substrates. Unlike several members of the receptor tyrosine kinase superfamily, which directly recruit and phosphorylate signaling/adapter proteins, the IR mainly signals by recruiting and phosphorylating members of the insulin receptor substrate family, IRS-1, -2, -3, and -4, Gab1 and -2, and p62dok-1, -2, and -3 (2, 3). These proteins then serve as multivalent docking sites for the recruitment of other Src homology domain 2-containing signaling proteins. Subsequently, at least two major signal transduction cascades are initiated including the mitogen-activated protein kinase-and phosphatidylinositol 3Ј-kinase-signaling pathways, which propagate the signal to various cytoplasmic and nuclear effectors (1, 4).Unlike the IR, cytokine receptors do not possess intrinsic tyrosine kinase activity. Instead, they depend upon receptorassociated Janus kinase tyrosine kinases to initiate signaling after ligand binding (5-7). These Janus kinases become activated and phosphorylate themselves, the cytokine receptor to which they are bound, and Src homology domain 2-containing signaling/adapter proteins, includin...

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“…Peterson et al, 1990 Kadonaga et al, 1987Jones et al, 1987Paonessa et al, 1988Landschulz et al, 1988Roesler et al, 1988Williams et al, 1988O'Brien & Granner, 1991Beato, 1989Bohman et al, 1987 a The sequence is located in the complementary strain.…”

Section: Cis-elementmentioning

confidence: 99%

The rat mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A‐synthase gene contains elements that mediate its multihormonal regulation and tissue specificity

Gil‐Gómez¹,

Ayté²,

Hegardt³

1993

European Journal of Biochemistry

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Mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A (HMG‐CoA) synthase, a liver‐specific enzyme, is a constituent of the HMG‐CoA cycle responsible for ketone‐body synthesis. We report the isolation and characterization of genomic clones that encompass the gene for rat mitochondrial HMG‐CoA synthase. The gene spans at least 24 kbp and contains ten exons and nine introns. The 5′ flanking region of the gene has also been cloned and characterized. Exon 1 contains the untranslated sequence of the transcript, extending downstream to enclose the coding region for the putative mitochondrial‐targeting signal (35 amino acids). The 1149‐bp proximal region of the transcription start point permits transcription of a reporter gene in transfected hepatoma cells but not in an extrahepatic cell line, confirming the function of the promoter. A truncated construct of 142 bp is still able to promote transcription in hepatoma cells, suggesting the presence of liver‐specific enhancer elements in the proximal promoter region. The 5′ flanking region contains typical promoter elements, including a TATA box and several putative recognition sequences for transcription factors involved in controlling both basal‐level and hormone‐modulated transcription rates. Furthermore, the presence in the mitochondrial HMG‐CoA‐synthase promoter of cis‐elements, responsible for the multihormonal regulation of transcription, is supported by transient transfection experiments.

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Regulation of gene expression by insulin

Cited by 271 publications

References 181 publications

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

Transcriptional control of genes that regulate glycolysis and gluconeogenesis in adult liver

Insulin Induction of SOCS-2 and SOCS-3 mRNA Expression in C2C12 Skeletal Muscle Cells Is Mediated by Stat5*

The rat mitochondrial 3‐hydroxy‐3‐methylglutaryl‐coenzyme‐A‐synthase gene contains elements that mediate its multihormonal regulation and tissue specificity

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