Role of CCAAT Enhancer-binding Protein β in the Thyroid Hormone and cAMP Induction of Phosphoenolpyruvate Carboxykinase Gene Transcription

Park, Edwards A.; Song, Shulan; Vinson, Charles; Roesler, William J.

doi:10.1074/jbc.274.1.211

Cited by 63 publications

(55 citation statements)

References 48 publications

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“…Prior work by our laboratory using GAL4-C/EBP fusion proteins suggested that either C/EBP isoform has the potential to mediate the cAMP response of PEPCK-C in liver (11). However, to date there has been no evidence in regards to which specific isoform mediates the cAMP responsiveness of the endogenous PEPCK-C gene in liver cells.…”

mentioning

confidence: 87%

“…In the case of the PEPCK promoter, C/EBPs assist in mediating the transcriptional effects of cAMP (26,37, this study), glucocorticoids (36, this study), and T3 (9,11). The production of stable rat hepatoma H4IIE cell lines, expressing molecules designed to inhibit the activity of C/EBP isoforms, have allowed us to assess the requirement of these transcription factors in various cellular processes.…”

Section: Figmentioning

confidence: 99%

“…This complex organization of DNA sequences and DNA-binding proteins likely allows for intricate control of tissue-specific expression and the integration of various signaling pathways. For example, the response of the PEPCK-C promoter to thyroid hormones is mediated not only by the binding of an activated thyroid hormone receptor to a typical thyroid hormone response element (9,10), but also requires one of the C/EBP binding sites utilized in the CRU (11). Thus, there is a potential integration of the thyroid hormone response and the cAMP response of the PEPCK-C promoter, brought about by this C/EBP molecule, which may account for the synergistic activation of the promoter by these two signaling pathways.…”

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confidence: 99%

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Hormonal Regulation of the Phosphoenolpyruvate Carboxykinase Gene

Crosson

Roesler

2000

Journal of Biological Chemistry

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The CCAAT/enhancer-binding protein ␣ (C/EBP) is a transcription factor that trans-activates a number of metabolically important genes. Previous work has demonstrated that C/EBP␣ and C/EBP␤ have the potential to mediate the cAMP responsiveness of phosphoenolpyruvate carboxykinase (PEPCK) in liver cells. However, these studies used GAL4 fusion proteins and artificial promoter-reporter gene vectors in transfection experiments; as a result, these studies only indicated that both isoforms had the potential to mediate the hormonal response and not which isoform actually participated in vivo. To address this issue, we produced hepatoma cell lines that stably expressed either a dominant negative inhibitor or antisense RNA for these two main liver C/EBP isoforms. Inhibition of all C/EBP isoforms via expression of the dominant negative protein eliminated cAMP responsiveness, and reduced glucocorticoid responsiveness, of the endogenous PEPCK gene in hepatoma cells. Antisense directed against C/EBP␣ mRNA, which reduced C/EBP␣ protein levels by nearly 80%, also significantly reduced the cAMP responsiveness of the endogenous PEPCK promoter, whereas antisense directed against C/EBP␤ was without effect. There was no major alteration in cAMP signaling in the C/EBP␣ antisense cells, as cAMP induction of the C/EBP␤ gene was similar to that in wild-type H4IIE cells. These data suggest that the ␣-isoform of C/EBP is specifically utilized for mediating the cAMP responsiveness of the PEPCK gene.

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confidence: 87%

Section: Figmentioning

confidence: 99%

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confidence: 99%

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Hormonal Regulation of the Phosphoenolpyruvate Carboxykinase Gene

Crosson

Roesler

2000

Journal of Biological Chemistry

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“…In adipose tissue, C/EBPβ is involved in the transcription of fat-specific genes (Christy et al, 1989;Yeh et al, 1995) and participates in the differentiation of pre-adipocytes (Bezy et al, 2007;Hamm et al, 2001). In addition, C/EBPβ regulates carbohydrate and lipid metabolism through binding and activating a variety of genes encoding key metabolic enzymes including, but not limited to, phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine aminotransferase (Garlatti et al, 1993;Park et al, 1990;Park et al, 1999;Wang et al, 1996), fatty acid synthesis enzyme acetyl-CoA carboxylase (Tae et al, 1994) and the albumin gene (Friedman et al, 1989).…”

Section: Ts and Downmentioning

confidence: 99%

“…Although detailed investigations have been performed to identify the mechanism by which T3 regulated different metabolic genes including phosphoenolpyruvate carboxykinase (PEPCK), carnitine palmitoyltransferase 1a (CPT-1a), apolipoprotein B (ApoB) and uncoupling protein 3 (UCP3) (de Lange et al, 2007;Jackson-Hayes et al, 2003;Mukhopadhyay et al, 2003;Park et al, 1999;Zhang et al, 2004b), the mechanism of the induction of the pyruvate dehydrogenase kinase 4 (PDK4) gene by T3 had not been identified (Sugden et al, 1996). Understanding the mechanism of activation of PDK4 by T3 is an important step to fully understand the metabolic effect of the T3 on fatty acid and glucose metabolism as PDK4 is a key regulator in the pyruvate metabolism, which in turn affects both glucose and fatty acid metabolism (Jeoung & Harris, 2008;).…”

Section: Thyroid Hormone Effects On Glucose and Fatty Acids Metabolismmentioning

confidence: 99%

Regulation of Pyruvate Dehydrogenase Kinase 4 by Thyroid Hormone / Role of Peroxisome Proliferator Activated Receptor Gamma Coactivator-1 alpha and Ccaat Enhancer Binding Protein

Attia¹

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Pyruvate dehydrogenase kinase 4 (PDK4) regulates pyruvate oxidation through the phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC). PDC catalyzes the conversion of pyruvate to acetyl‐CoA and is an important control point in glucose and pyruvate metabolism. PDK4 gene expression is stimulated by thyroid hormone (T3), glucocorticoids and long chain fatty acids. Here, we have identified two binding sites for the thyroid hormone receptor (TRß) in the promoter of the PDK4 gene. In addition, we have investigated the role of transcriptional coactivators and found that the peroxisome proliferator activated receptor gamma coactivator (PGC‐1α) enhances the T3 induction of PDK4. Addition of T3 to rat hepatocytes increased the abundance of the PGC‐1α and its association with the PDK4 promoter. Administration of T3 to hypothyroid rats increased PGC‐1α protein levels in the liver. In addition, we observed enhanced association of PGC‐1α not only with the PDK4 gene but also with phosphoenolpyruvate carboxykinase (PEPCK) and carnitine palmitoyltransferase 1a (CPT‐1a) genes. Knock‐down of PGC‐1α in rat hepatocytes reduced the T3 induction of PDK4, PEPCK and CPT‐1a genes. Our results indicate that T3 regulates PGC‐1α abundance and association with hepatic genes and in turn PGC‐1α is an important participant in the T3 induction of selected genes.

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Gluconeogenesis

Wattanavanitchakorn

Jitrapakdee

2016

Encyclopedia of Life Sciences

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Gluconeogenesis is a pivotal biochemical pathway in which glucose is synthesised from non‐carbohydrate precursors, that is, lactate, alanine, glutamine and glycerol, during prolonged starvation. This pathway utilises most glycolytic enzymes in the reverse direction, except the three irreversible steps, which are bypassed by four additional enzymes, pyruvate carboxylase (PC), phosphoeonolpyruvate carboxykinase (PEPCK), fructose‐1,6‐bisphosphatase (FBPase) and glucose‐6‐phosphatase (G6Pase), known as the ‘gluconeogenic enzymes’. Elevated levels of glucagon and glucocorticoids during prolonged fasting stimulate gluconeogenesis in the short and long term. A short‐term response to these hormones involves reversible phosphorylation and allosteric modifications, which can alter the activities of the gluconeogenic enzymes. In contrast, a long‐term response involves the modulation of transcriptional activity of their (nuclear) encoded genes. CREB (cAMP‐responsive element binding protein), FoxO1 (forkhead box O1), PPARα (peroxisome proliferator activated receptor alpha) and PGC1α (peroxisome proliferator activated‐receptor gamma coactivator‐1α) are the key transcription factors that control most gluconeogenic enzymes. Deregulation of glucogeneogic enzymes perturbs systemic glucose homeostasis, causing diabetes. Key Concepts Mammals are well adapted to nutrient deprivation in order to survive during food restriction. Glucose is the sole energy source for brain and red blood cells. Alteration of glucoregulatory hormones during starvation influences glucose production from liver and kidney by programming relevant biochemical pathways. Binding of glucoregulatory hormones to their receptors transmits the biochemical signals or molecules that affect the activity of key gluconeogenic enzymes or transcription of gluconeogenic genes. Loss‐of‐function mutations of gluconeogenic enzyme genes or deregulation of gluconeogenic pathway results in the failure of the body to maintain glucose homeostasis

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Role of CCAAT Enhancer-binding Protein β in the Thyroid Hormone and cAMP Induction of Phosphoenolpyruvate Carboxykinase Gene Transcription

Cited by 63 publications

References 48 publications

Hormonal Regulation of the Phosphoenolpyruvate Carboxykinase Gene

Hormonal Regulation of the Phosphoenolpyruvate Carboxykinase Gene

Regulation of Pyruvate Dehydrogenase Kinase 4 by Thyroid Hormone / Role of Peroxisome Proliferator Activated Receptor Gamma Coactivator-1 alpha and Ccaat Enhancer Binding Protein

Gluconeogenesis

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