Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cholera toxin (CT) on the growth of 12 small cell lung carcinoma (SCLC) and 15 non-small cell lung carcinoma (NSCLC) cell lines is presented. CT inhibited the growth of nine SCLC cell lines (concentration for 50% inhibition of growth, 27-700 ng/ml), all of which had abundant expression of GM1 ganglioside, the surface receptor for CT. CT-resistant SCLC all had greatly decreased GM1 expression. In contrast, CT inhibited the growth of only four of 15 NSCLC cell lines. Seven of the 11 CT-resistant NSCLC had levels of GM1 comparable to CT-sensitive NSCLC or SCLC. In a limited panel of cell lines, cyclic AMP (cAMP) agonists including forskolin, 8Br[cAMP], and dibutyryl[cAMP] did not consistently reproduce CT-mediated inhibition of cell growth, nor did these compounds overcome resistance of cells to the growth inhibitory effects of CT. Expression of the RI and RII regulatory subunits of cAMP-dependent protein kinase was similar in CT-resistant and CT-sensitive SCLC or NSCLC cell lines. In the presence of isobutylmethylxanthine, intracellular cAMP levels induced by CT in a CT-resistant, GM1(+) NSCLC cell line were comparable to those achieved in a CT-sensitive NSCLC cell line. We conclude that inhibition of lung carcinoma cell growth by CT in all cases requires expression of GM1, and in the case of SCLC cell lines the presence of GM1 is sufficient. In NSCLC cell lines, expression of GM1 is not sufficient for growth inhibition by CT. These findings imply refractoriness to growth inhibition by cAMP in GM1(+), CT-resistant NSCLC cell lines and the possibility of non-cAMP-related mechanisms for growth inhibition in CT-sensitive cell lines.
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PMID:Growth inhibition by cholera toxin of human lung carcinoma cell lines: correlation with GM1 ganglioside expression. 137 68

Gangliosides have profound effects on the phosphorylation of several proteins in myelin. Addition of polysialogangliosides to purified guinea pig brain myelin enhanced the endogenous phosphorylation of a 62-kDa phosphoprotein, but completely inhibited the phosphorylation of myelin basic protein (MBP) (18.5 kDa). The ganglioside-stimulated phosphorylation of the 62-kDa protein was dose-dependent and -specific. Asialo-GM1, ceramide trihexosides, N-acetylneuraminic acid, or colominic acid alone could not mimic this effect, suggesting that the activation process requires both the hydrophobic head group and the anionic character of the gangliosides. Studies on the time course of this reaction revealed that it was a rapid and reversible process and was affected only very slightly by Ca2+. Thus, the stimulatory effect of gangliosides may not involve Ca2+-gangliosides complexes or proteolysis, but may be mediated through an activation of a ganglioside-dependent protein kinase or due to substrate protein-glycolipid interaction. Modulation of the phosphorylation of MBP by gangliosides varies with the states of phosphorylation of this protein. Prior addition of ganglioside to myelin inhibited the phosphorylation of MBP. However, addition of gangliosides to myelin subsequent to maximal phosphorylation of MBP retarded the dephosphorylation of this protein. Phosphorylation of isolated MBP by protein kinase C was stimulated by gangliosides, provided phosphatidylserine was present. In contrast, the glycolipid inhibited the phosphorylation of a unique site catalyzed by cAMP-dependent protein kinase. This site was distinct from those phosphorylated by protein kinase C and was also sensitive to chymotryptic cleavage. Although the exact physiological significance of protein phosphorylation in myelin has yet to be established, gangliosides may play an important role in the modulation of this reversible post-translational modification mechanism.
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PMID:Ganglioside-modulated protein phosphorylation in myelin. 243 83

The holoenzyme of cAMP-dependent protein kinase (cAMP-kinase) partially purified from the particulate fraction of rat brain was stimulated by gangliosides. Among various gangliosides tested, GM1 was most potent, giving Ka value of 19.5 microM. The maximal activation of the kinase was obtained with 100 microM GM1 using kemptide as substrate. Gangliosides inhibited the kinase activity of the catalytic subunit of cAMP-kinase. Of various substrates tested, the ganglioside-stimulated cAMP-kinase could phosphorylate microtubule-associated protein 2, synapsin I and myelin basic protein, but not histone H1 and casein. The molecular mechanisms of the stimulatory effect of gangliosides were investigated. The kinase activated with GM1 was inhibited by the addition of PKItide, a specific inhibitor for cAMP-kinase. However, GM1 did not dissociate the holoenzyme into the catalytic and regulatory subunits and did not interfere with the binding ability of cAMP to the holoenzyme. These results suggest that the gangliosides can directly activate cAMP-kinase in a different manner from cAMP.
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PMID:Stimulation of cyclic adenosine 3',5'-monophosphate-dependent protein kinase with brain gangliosides. 759 39

Prostaglandin (PG) D2 and PGE2 receptor binding activities are regulated in various fashions. The protein phosphorylation by exogenous cAMP-dependent protein kinase or calmodulin-dependent protein kinase II significantly increased PGE2 binding activity through an increase in the apparent amount of the maximal binding, suggesting that the PGE2 receptor may be regulated through protein phosphorylation-dephosphorylation. Other possible regulatory mechanisms were found as the result of studies on functional modification of glycoconjugates. Pretreatment with glycoprotein-specific endoglycosidases (peptide N-glycohydrolase F, endo-alpha-N-acetylgalactosaminidase) decreased both PGD2 and PGE2 receptor binding activities and consequently these activities became nonspecific ones. In addition, these binding activities were increased by the addition of a ganglioside or cerebroside mixture, but not ceramide. The addition of separate purified glycolipids showed more specifically their effect on each PG binding. PGD2 binding activity was increased by GD1a and GQ1b and decreased by GM1 and GT1a, while PGE2 binding activity was increased by GQ1b and galactocerebroside. In such a way, PG receptors may require some specific microenvironment for their maximal binding activity.
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PMID:Regulation of prostaglandin D2 and E2 receptor binding in the central nervous system. 839 54