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Metabolic control of gluconeogenesis in transgenic mice: Regulation of the phosphoenolpyruvate carboxykinase gene
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The enzyme phosphoenolpyruvate carboxykinase (PEPCK) is the key regulatory enzyme in gluconeogenesis, the bridge between the Krebs cycle and glucose synthesis, catalyzing the conversion of oxaloacetate to phosphoenolpyruvate. It is tissue specific and found in liver, kidney, jejunum, adipose, and mammary tissue. Hormones exert both positive and negative control of its activity, of the level of the enzyme protein, and of the expression of its mRNA. The very short half-life of the enzyme's mRNA (30 minutes) allows for rapid hormonal control of gluconeogenesis.
The PEPCK gene promoter has a relatively short stretch (base pairs -460 to +73 relative to the start site transcription) containing the hormone-responsive (regulatory) elements that control expression of this gene. In response to hormones, nuclear receptor hormones (transcription factors) bind to the regulatory elements. There may exist multiple regulatory sites on the promoter for each type of regulatory protein.
The following are the regulating hormones for PEPCK gene transcription (Figure 1):
1) cAMP: The level of tissue cAMP is controlled by glucagon. In response to cAMP, one of the cAMP-dependent transcription factors, C/EBP or CREB, bind to the domain CRE (cAMP-response element). Other related factors bind to domain P2 (-200 to -164) and the important domain P3(I)(-248 to -230). Accessory factors bind to domains P4, P5, and P6.(1) (Figure 1 omitted)
2) Glucocorticoids: Glucocorticoid receptors induce PEPCK gene transcription, with a binding site within the glucocorticoid response element (between -450 and -400).(2)
3) Insulin has an inhibitory effect on PEPCK gene transcription, with a binding site within the glucocorticoid response element (-416 to -407).(2)
4) Thyroid hormone: Thyroid hormone receptor binds at -332 to -308, inducing PEPCK mRNA.(3) The activation of transcription by the binding of the thyroid hormone receptor to the hormone-response element results in synergistic interaction with cAMP-stimulated binding of C/EBP and CREB to the...