Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of calcium signalling and specific intracellular calcium signalling pathways in regulating skeletal muscle tissue peroxisome proliferator-activated receptor gamma co-activator (PGC)-1alpha, hexokinase (HK)II and pyruvate dehydrogenase kinase (PDK)4 mRNA was examined. Cultured primary rat skeletal muscle cells were incubated for 6 h in caffeine or ionomycin. Because PGC-1alpha mRNA clearly showed greater induction with ionomycin, the latter was chosen for the main experiments, whereby cells were incubated for 6 h with either ionomycin alone or in combination with either cyclosporin A or KN-62. The PGC-1alpha mRNA level was increased (p<0.05) approximately six-fold and HKII mRNA content approximately two-fold by ionomycin relative to the corresponding controls, whereas the PDK4 mRNA content remained unaffected. Cyclosporin A abolished (p<0.05) and KN-62 reduced (p<0.1) the ionomycin-induced increase in PGC-1alpha mRNA. Electrical stimulation of in vitro incubated rat EDL muscle increased (p<0.05) PGC-1alpha mRNA by 2.2-fold after 4 h of recovery relative to a resting control, and this increase was absent when muscles were incubated with KN-62 or cyclosporin A. The present data strongly suggest that calcium signalling is involved in regulating the PGC-1alpha and HKII genes, but not PDK4. Both calcineurin and CaMK signalling seem to be involved in the calcium- and contraction-mediated PGC-1alpha up-regulation in skeletal muscle.
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PMID:Calcium signalling in the regulation of PGC-1alpha, PDK4 and HKII mRNA expression. 1751 43

The ability of calcineurin to regulate IRS-1 and IRS-2 levels has not been examined in any given cells, although calcineurin inhibition by therapeutic immunosuppressants produced cytoprotective and cytotoxic effects (e.g., new-onset of diabetes mellitus, seizure). Chronic (>or=3h) treatment of cultured bovine adrenal chromaffin cells with cyclosporin A or FK506 decreased IRS-2 protein level by approximately 50% (IC(50)=200 or 10nM), without changing IRS-2 mRNA level, and insulin receptor, insulin-like growth factor-I (IGF-I) receptor, IRS-1, PI3K/PDK-1/Akt/GSK-3beta and ERK1/ERK2 protein levels. When the cells were washed to remove the test drug, the decreased IRS-2 level restored to the control level. Cyclosporin A or FK506 treatment inhibited calcineurin activity (IC(50)=500 or 40 nM, in vitro assay). Rapamycin, an FK506-binding protein ligand unable to inhibit calcineurin, failed to decrease IRS-2, but reversed FK506-induced decreases of calcineurin activity and IRS-2 level. Pulse-label followed by polyacrylamide gel electrophoresis revealed that cyclosporin A or FK506 accelerated IRS-2 degradation rate (t(1/2)) from >24 to approximately 4.2h, without altering IRS-2 synthesis. IRS-2 reduction by cyclosporin A or FK506 was prevented by lactacystin (proteasome inhibitor), but not by calpeptin (calpain inhibitor) or leupeptin (lysosome inhibitor). Cyclosporin A or FK506 increased serine-phosphorylation and ubiquitination of IRS-2. Cell surface (125)I-IGF-I binding capacity was not changed in cyclosporin A- or FK506-treated cells; however, IGF-I-induced phosphorylations of GSK-3beta and ERK1/ERK2 were attenuated by approximately 50%, which were prevented by rapamycin or lactacystin. Thus, calcineurin inhibition decreased IRS-2 level via proteasomal IRS-2 degradation, attenuating IGF-I-induced GSK-3beta and ERK pathways.
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PMID:Proteasomal degradation of IRS-2, but not IRS-1 by calcineurin inhibition: attenuation of insulin-like growth factor-I-induced GSK-3beta and ERK pathways in adrenal chromaffin cells. 1853 59