Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gene for acetyl-CoA carboxylase, the rate-limiting enzyme in the biogenesis of long chain fatty acids, contains two promoter regions which control the generation of different forms of carboxylase mRNA. At least five different forms of carboxylase mRNA are generated by differential splicing of the two transcripts formed under the influence of two promoters. One of the two promoters is mainly responsible for the generation of a class of carboxylase mRNA species, pAU type, induced tissue specifically under lipogenic conditions; the other generates ACC mRNAs (FL-type) which are expressed under normal conditions but this expression is also stimulated under lipogenic conditions. In the present studies, we have characterized the promoter that is responsible for the FL-type of ACC mRNA. This promoter contains no TATA or CAAT boxes, but five G/C motifs whose sequences are typical of transcriptional factor Sp1 binding sites. However, the presence of these G/C motifs is not sufficient to drive the transcription of the gene under the control of this promoter. Expression of promoter activity requires three copies of 11 to 13mer enhancer elements which are located in the region upstream to the G/C motifs. The presence of such enhancer elements in a house-keeping gene is unusual, and provides a new example where an enhancer element occurs in the CpG island-type promoter of a house-keeping gene.
 ...
PMID:An enhancer element in the house-keeping promoter for acetyl-CoA carboxylase gene. 197 62

Acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the biosynthesis of fatty acids, is induced in the presence of high glucose levels. The ACC gene contains two promoters: promoter I (PI) expression is inducible under lipogenic conditions, while promoter II (PII) expression, even though constitutively expressed in all tissues, is also controlled under various physiological conditions. Examination of the expression pattern of a series of deletion constructs of PII showed that the region from -340 to -249 was essential for ACC induction. In addition, by electrophoretic mobility shift assays, supershift assays, and DNase I footprinting studies, we have detected the binding of the transcription factor Sp1 at the two GC-rich sequences located within the -340 to -249 region of promoter II. Mutations at the GC-rich sequences prevented binding of Sp1, and the induction of the PII promoter was no longer observed. Cotransfection studies, in Drosophila Schneider SL2 cells, with the Sp1 expression vector and PII-CAT constructs, have further confirmed the activation of promoter II by Sp1. In addition, we have identified Sp3, another member of the Sp1 family of transcription factors, as a second factor that can bind to the glucose response elements of PII.
 ...
PMID:Sp1 mediates glucose activation of the acetyl-CoA carboxylase promoter. 857 28

When mouse 30A5 preadipocytes are exposed to high glucose concentrations, acetyl-CoA carboxylase is induced through glucose activation of promoter II of the acetyl-CoA carboxylase gene. Glucose treatment of the cells increases Sp1 binding to two GC-rich glucose response elements in promoter II. We have investigated the mechanism by which glucose increases Sp1 binding and transactivation of promoter II in 30A5 cells. DNA mobility shift assays have shown that nuclear extracts from glucose-treated cells exhibit increased Sp1 binding activity. This increase in the binding activity is not due to glucose-mediated changes in the amount of Sp1 in the nucleus but to an increase in the activity that modifies Sp1 so that it binds more effectively to the promoter sequence. This Sp1 modifying activity is inhibited by okadaic acid and phosphatase inhibitor 2, and has a molecular mass of 38-42 kDa. The catalytic subunit of type 1 protein phosphatase, whose molecular mass is 38 kDa, also increased the ability of Sp1 to bind to promoter II. Treatment of nuclear extract with antibodies against the catalytic subunit partially suppressed the nuclear activity for Sp1 activation. From these results, we conclude that the Sp1 transcription factor exhibits enhanced binding to promoter II and transcriptional activation is the result of glucose-induced dephosphorylation by type 1 phosphatase.
 ...
PMID:Dephosphorylation of Sp1 by protein phosphatase 1 is involved in the glucose-mediated activation of the acetyl-CoA carboxylase gene. 866 83

It has been suggested that, in pancreatic beta-cells, acetyl-CoA carboxylase (ACC) is a key enzyme in glucose signal transduction leading to glucose-induced insulin secretion. The PII promoter is the only active promoter for the ACC gene in the beta-cell. Here we report that, in the pancreatic beta-cell, high glucose levels (above 20 mm) activate Sp1 binding to the glucose response element of the PII promoter, which leads to a dose-dependent increase in PII transcription. The expression of a gene coding protein kinase CK2 (CK2) alpha subunit, or the presence of okadaic acid (a serine/threonine protein phosphatase inhibitor), partially blocks the glucose activation of PII transcription. The inhibitory effect of CK2 alpha, or okadaic acid, was not observed in the absence of glucose or at low glucose concentrations. Phosphorylation of Sp1 by CK2 alpha leads to the inactivation of Sp1 binding to PII. Dephosphorylation of the phosphorylated Sp1 by protein phosphatase 1 (PP1) activates the binding of Sp1 to PII. Inhibition of PP1-catalyzed Sp1 dephosphorylation by okadaic acid, or PP1 specific inhibitor 2, decreases Sp1 binding to PII. These results suggest that the phosphorylation/dephosphorylation of Sp1 by CK2/PP1 may be the underlying mechanism by which the expression of the PII promoter of ACC is controlled in the process of glucose-mediated insulin secretion in pancreatic beta-cells.
 ...
PMID:Protein kinase CK2 down-regulates glucose-activated expression of the acetyl-CoA carboxylase gene. 902 76

The product of the retinoblastoma (Rb) susceptibility gene ( RB-1 ) regulates expression of a variety of growth control genes via discrete promoter elements termed retinoblastoma control elements (RCEs). We have previously shown that RCEs are bound and regulated by a common set of ubiquitously expressed nuclear proteins of 115, 95 and 80 kDa, termed retinoblastoma control proteins (RCPs). We have also previously determined that Sp3 and Sp1, two members of the Sp family of transcription factors, encode the 115 and 95 kDa RCPs respectively and that Rb stimulates Sp1/Sp3-mediated transcription in vivo. In this report we have extended these results by determining that the 80 kDa RCP arises from Sp3 mRNA via translational initiation at two internal sites located within the Sp3 trans -activation domain. Internally initiated Sp3 proteins readily bind to Sp1 binding sites in vitro yet have little or no capacity to stimulate transcription of Sp-regulated genes in vivo. Instead, these Sp3-derived proteins function as potent inhibitors of Sp1/Sp3- mediated transcription. Since cell cycle- or signal- induced expression of a variety of genes, including p21 waf1/cip1, p15 INK4B, CYP11A, mdr1 and acetyl-CoA carboxylase, have been mapped to GC-rich promoter elements that bind Sp family members, we speculate that alterations of the protein and/or DNA binding activities of internally initiated Sp3 isoforms may account in part for the regulation of such differentially expressed genes.
 ...
PMID:Sp3 encodes multiple proteins that differ in their capacity to stimulate or repress transcription. 922 12

Cellular cholesterol and fatty acid levels are coordinately regulated by a family of transcriptional regulatory proteins designated sterol regulatory element binding proteins (SREBPs). SREBP-dependent transcriptional activation from all promoters examined thus far is dependent on the presence of an additional binding site for a ubiquitous coactivator. In the low-density lipoprotein (LDL) receptor, acetyl coenzyme A carboxylase (ACC), and fatty acid synthase (FAS) promoters, which are all regulated by SREBP, the coactivator is the transcription factor Sp1. In this report, we demonstrate that Sp3, another member of the Sp1 family, is capable of substituting for Sp1 in coactivating transcription from all three of these promoters. Results of an earlier study showed that efficient activation of transcription from the LDL receptor promoter required domain C of Sp1; however, this domain is not crucial for activation of the simian virus 40 promoter, where synergistic activation occurs through multiple Sp1 binding sites and does not require SREBP. Also in the present report, we further localize the critical determinant of the C domain required for activation of the LDL receptor to a small region that is highly conserved between Sp1 and Sp3. This crucial domain encompasses the buttonhead box, which is a 10-amino-acid stretch that is present in several Sp1 family members, including the Drosophila buttonhead gene product. Interestingly, neither the buttonhead box nor the entire C domain is required for the activation of the FAS and ACC promoters even though both SREBP and Sp1 are critical players. ACC and FAS each contain two critical SREBP sites, whereas there is only one in the LDL receptor promoter. This finding suggested that buttonhead-dependent activation by SREBP and Sp1 may be limited to promoters that naturally contain a single SREBP recognition site. Consistent with this model, a synthetic construct containing three tandem copies of the native LDL receptor SREBP site linked to a single Sp1 site was also significantly activated in a buttonhead-independent fashion. Taken together, these studies indicate that transcriptional activation through the concerted action of SREBP and Sp1 can occur by at least two different mechanisms, and promoters that are activated by each one can potentially be identified by the number of critical SREBP binding sites that they contain.
 ...
PMID:Promoter selective transcriptional synergy mediated by sterol regulatory element binding protein and Sp1: a critical role for the Btd domain of Sp1. 927 97

The sterol regulatory element binding proteins (SREBPs) are central regulators of lipid homeostasis in mammalian cells. Their activity is controlled by a sterol-regulated two-step proteolytic process that releases the nuclear targeted amino-terminal domain from the membrane anchored carboxyl-terminal remnant. This ensures that transcriptional stimulation of the appropriate genes occurs only when increased intracellular sterol accumulation is required. Gene targets for SREBP encode key proteins of cholesterol metabolism as well as essential proteins of fatty acid biosynthesis, providing a mechanism for coordinate control of these two major lipid pathways when sterols and fatty acids need to accumulate together. However, the regulatory mechanism must provide a way to uncouple these two pathways to allow separate regulation when sterol or fat levels need to increase independently of each other. We compared the similarities and differences for how SREBP activates the promoter for the low density lipoprotein (LDL) receptor, which is the key protein involved in cholesterol uptake, relative to how it activates promoters for acetyl coenzyme A carboxylase (ACC) and fatty acid synthase (FAS), which are both key enzymes of fatty acid biosynthesis. In the current studies we show there are two distinct sites for SREBP binding that control activation of the ACC PII promoter whereas previous work has shown there is only a single SREBP site in the LDL receptor. Additionally, disruption of either ACC site results in a total loss in promoter function and a severe decrease in SREBP binding even to the neighboring unaltered site. Thus, the two sites are equally important and dependent on one another for optimal function. This is in contrast to the FAS promoter where SREBP binds to two adjacent sites independently and the one located closer to the binding site for the Sp1 co-regulator is more critical for sterol regulation and activation by SREBP over-expression.
 ...
PMID:Sterol regulation of acetyl coenzyme A carboxylase promoter requires two interdependent binding sites for sterol regulatory element binding proteins. 930 Jul 85

When two copies of the sequences spanning -57 to -35 of the fatty acid synthase (FAS) or -64 to -41 of the ATP citrate-lyase (ACL) gene linked to a reporter gene were transfected into primary cultured hepatocytes, the reporter activities significantly increased in response to insulin/glucose treatment. In cotransfection experiments of the FAS(-57/-35) with the Sp1 or Sp3 expression vector, the reporter activities of transcription were suppressed by Sp1 and stimulated by Sp3. In the cotransfection experiments of ACL(-64/-41), the activities were suppressed by Sp1 but were unchanged by Sp3. A similar effect of Sp1 and Sp3 on transcription was seen in mRNA concentrations and enzyme activities of endogenous FAS and ACL. Moreover, the mRNA concentrations and enzyme activities of endogenous acetyl-CoA carboxylase were suppressed by Sp1 and greatly increased by Sp3. Gel mobility super shift assays using antibodies against Sp1 or Sp3 revealed the binding of the transcription factors Sp1 and Sp3 with the GC rich regions located within FAS(-57/-35) and ACL(-64/-41) genes. The formation of DNA-protein complexes was decreased in rats fed a high-carbohydrate diet in comparison with that in fasted rats, but feeding the corn oil diet inhibited this decrease. In Western immunoblotting assay, however, the amount of Sp1 and Sp3 remained unchanged in the dietary conditions. Therefore, the binding of DNA-protein complexes was not due to changes in the amount of Sp1 and Sp3 but to changes in the binding activity, suggesting that these transcription factors may be an important determinant of lipogenic enzyme expression.
 ...
PMID:Transcriptional regulation of fatty acid synthase gene and ATP citrate-lyase gene by Sp1 and Sp3 in rat hepatocytes(1). 1061 88

Acetyl-CoA carboxylase (ACC) exists as two major isoforms originated from separate genes: ACCalpha (or ACC1) and ACCbeta (or ACC2). Previous data revealed that ACCbeta has two forms of mRNA with different 5'-untranslated regions derived by different usage of promoters, I and II, in human. In this study, we revealed that ACCbeta expression in liver is markedly stimulated by food intake at the transcriptional level. In the process of this induction in rat liver, promoter II plays the major role in regulating the expression of ACCbeta gene. The transient transfection with promoter II-luciferase reporters elucidated that the region from -93 to -38 nucleotides is important for the responsiveness to sterol regulatory element-binding protein-1 (SREBP-1), which is known to be the principle mediator for the stimulation of gene transcriptions by insulin and diet. The Sp1-binding site (-71 to -66) and neighboring two conserved SREs (-62 to -44) play a critical role in the stimulation of ACCbeta gene expression by SREBP-1. In vivo chromatin immunoprecipitation assay revealed that SREBP-1 directly bound to ACCbeta promoter II in liver, and its binding was regulated by the diet. This study provides evidence that ACCbeta expression in liver is regulated at the transcriptional level by the direct interaction of SREBP-1 with promoter II.
 ...
PMID:Acetyl-CoA carboxylase beta gene is regulated by sterol regulatory element-binding protein-1 in liver. 1276 44

Hepatic steatosis is common in obese individuals with hyperinsulinemia and is an important hepatic manifestation of metabolic syndrome. Sterol regulatory binding protein-1c (SREBP-1c) is a master regulator of lipogenic gene expression in the liver. Hyperinsulinemia induces transcription of SREBP-1c via activation of liver X receptor (LXR) and specificity protein 1 (Sp1). Cilostazol is an antiplatelet agent that prevents atherosclerosis and decreases serum triglyceride levels. However, little is known about the effects of cilostazol on hepatic lipogenesis. Here, we examined the role of cilostazol in the regulation of SREBP-1c transcription in the liver. The effects of cilostazol on the expression of SREBP-1c and its target genes in response to insulin or an LXR agonist (T0901317) were examined using real-time RT-PCR and western blot analysis on cultured hepatocytes. To investigate the effect of cilostazol on SREBP-1c at the transcriptional level, transient transfection reporter assays and electrophoretic mobility shift assays (EMSAs) were performed. Cilostazol inhibited insulin-induced and LXR-agonist-induced expression of SREBP-1c and its downstream targets, acetyl-CoA carboxylase and fatty acid synthase, in cultured hepatocytes. Cilostazol also inhibited activation of the SREBP-1c promoter by insulin, T0901317 and Sp1 in a luciferase reporter assay. EMSA analysis showed that cilostazol inhibits SREBP-1c expression by repressing the binding of LXR and Sp1 to the promoter region. These results indicate that cilostazol inhibits insulin-induced hepatic SREBP-1c expression via the inhibition of LXR and Sp1 activity and that cilostazol is a negative regulator of hepatic lipogenesis.
...
PMID:Cilostazol inhibits insulin-stimulated expression of sterol regulatory binding protein-1c via inhibition of LXR and Sp1. 2445 33


1