Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of fetal hepatocytes from 21-day-old rats with permeant derivatives of cyclic AMP (cAMP) or glucagon, increased the mRNA levels of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK-2/FBPase-2), L-pyruvate kinase (L-PK) and phosphoenolpyruvate carboxykinase (PEPCK). Contrary to this behavior, adult hepatocytes exhibited a decrease in the PFK-2/FBPase-2 and L-PK mRNA levels when incubated under equivalent experimental conditions. Dexamethasone also increased the PFK-2/FBPase-2 mRNA levels and costimulation of fetal hepatocytes with dexamethasone and a permeant analogue of cyclic AMP enhanced the levels of PFK-2/FBPase-2 mRNA, a situation opposite to that exhibited by adult hepatocytes. Treatment of the hepatocytes with transcriptional and translational inhibitors also produced differential responses in both types of cells. The PFK-2/FBPase-2 mRNA in fetal hepatocytes was more stable than in the adult cells. These results suggest that specific transcriptional factors and regulatory pathways differentially operate in fetal and adult hepatocytes in the control of the responses of carbohydrate metabolism to cAMP.
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PMID:Differential regulation of the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and pyruvate kinase by cyclic adenosine 3',5'-monophosphate in fetal and adult hepatocytes. 759 43

Covalent modification provides a mechanism for modulating molecular state and regulating physiology. A cycle of competing enzymes that add and remove a single modification can act as a molecular switch between "on" and "off" and has been widely studied as a core motif in systems biology. Here, we exploit the recently developed "linear framework" for time scale separation to determine the general principles of such switches. These methods are not limited to Michaelis-Menten assumptions, and our conclusions hold for enzymes whose mechanisms may be arbitrarily complicated. We show that switching efficiency improves with increasing irreversibility of the enzymes and that the on/off transition occurs when the ratio of enzyme levels reaches a value that depends only on the rate constants. Fluctuations in enzyme levels, which habitually occur due to cellular heterogeneity, can cause flipping back and forth between on and off, leading to incoherent mosaic behavior in tissues, that worsens as switching becomes sharper. This trade-off can be circumvented if enzyme levels are correlated. In particular, if the competing catalytic domains are on the same protein but do not influence each other, the resulting bifunctional enzyme can switch sharply while remaining coherent. In the mammalian liver, the switch between glycolysis and gluconeogenesis is regulated by the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). We suggest that bifunctionality of PFK-2/FBPase-2 complements the metabolic zonation of the liver by ensuring coherent switching in response to insulin and glucagon.
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PMID:A fundamental trade-off in covalent switching and its circumvention by enzyme bifunctionality in glucose homeostasis. 2463 22