Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of p44/42 mitogen-activated protein kinase (MAPK) in the induction of ornithine decarboxylase (ODC) was investigated by using PD98059, a specific MAPK-kinase (MEK1/2) inhibitor, and other signal-transduction inhibitors. In d,l-alpha-difluoromethylornithine (DFMO)-resistant L1210 cells stimulated to grow from quiescence, treatment with PD98059 inhibited p44/42 MAPK phosphorylation and the induction of ODC activity and protein. A marked reduction of the accumulation of mature ODC mRNA and its intron-containing precursor was observed, whereas ODC turnover was hardly affected. PD98059 also reduced the content of antizyme, but not that of antizyme mRNA. U0126, a novel and more potent inhibitor of MEK1/2, provoked a dose-dependent inhibition of ODC induction at lower concentrations with respect to PD98059. Other effective inhibitors of ODC induction proved to be genistein, manumycin A, herbimycin A, LY294002, wortmannin and KT5823, suggesting the involvement of other key proteins of signal-transduction pathways, i.e. Ras, Src, phosphatidylinositol 3-kinase and cGMP-dependent protein kinase, which may have a positive impact on MAPK. Cells kept in a DFMO-free medium, and thus containing high levels of putrescine and spermidine, showed enhanced MAPK phosphorylation and lower sensitivity to PD98059, compared with cells maintained in the presence of DFMO. In conclusion, these results indicate that the activation of p44/42 MAPK may favour the expression of ODC, and that polyamines, in turn, may affect the phosphorylation state of MAPK.
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PMID:p44/42 mitogen-activated protein kinase is involved in the expression of ornithine decarboxylase in leukaemia L1210 cells. 1039 94

C-type natriuretic peptide (CNP) and endothelin-1 are paracrine peptides with opposing effects on cardiac myocyte contraction and intracellular cGMP production. Elevated levels of both endothelin-1 and CNP are found in patients with congestive heart failure. These factors may be related to positive and negative regulation of cell apoptosis in the failing heart. To evaluate the effect of CNP and endothelin-1 on apoptosis of cardiac myocytes and the possible mechanisms involved, primary cardiac myocytes were prepared from neonatal Sabra rats. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Annexin V in situ staining. The TUNEL method was used to measure the apoptotic index. CNP and the cGMP derivative, 8-br-cGMP, induced apoptosis of cardiac myocytes. CNP-induced apoptosis could be blocked by HS 142-1 (a mixture of 20-30 kinds of linear beta-1, 6-glucan esterified by capronic acid, an antagonist of type A and B natriuretic peptide receptors), and KT 5823 (C29H25N3O5), the inhibitor of cGMP-dependent protein kinase). Alpha-difluoromethylornithine (DFMO), the irreversible inhibitor of ornithine decarboxylase, also induced apoptosis to a similar extent. CNP and 8-br-cGMP caused a marked reduction of intracellular ornithine decarboxylase expression, as determined by Western blot analysis and immunohistochemical assay. Preincubation with endothelin-1 attenuated CNP- and 8-br-cGMP-induced cardiomyocyte apoptosis. Endothelin-1 also antagonized the CNP- and 8-br-cGMP-induced reduction of intracellular ornithine decarboxylase expression. These results suggest that CNP has a proapoptotic effect on neonatal rat cardiac myocytes. The effect is mediated via natriuretic peptide receptors and is due to an elevation of intracellular cGMP, which reduces the expression of intracellular ornithine decarboxylase and probably the production of polyamines. Endothelin-1 protects cardiac myocytes against CNP-induced apoptosis by influencing the cGMP-dependent pathway, and this effect is probably mediated through both a reduction of cGMP and antagonism of the CNP-induced reduction of intracellular ornithine decarboxylase expression.
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PMID:The opposing effects of endothelin-1 and C-type natriuretic peptide on apoptosis of neonatal rat cardiac myocytes. 1290 91