Disease relevance of MAPK8

• Although the stress-activated protein kinase/c-Jun NH(2)-terminal kinase (JNK) signaling pathway is activated in response to CDDP toxicity, intracochlear perfusion of d-JNKI-1, a JNK inhibitor, did not protect against CDDP ototoxicity but instead potentiated the ototoxic effects of CDDP [1].
• Nitric oxide-mediated activation of extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) during hypoxia in cerebral cortical nuclei of newborn piglets [2].
• At 8 min of the sustained ischemia, p38, ERK, and p54 JNK phosphorylation were increased with no difference between groups (medians: p38: 207% of baseline in group 1 vs. 153% in group 2; ERK: 142 vs. 144%; p54 JNK: 171 vs. 155%, respectively) [3].
• Differential activation of ERK, p38, and JNK MAPK by nociceptin/orphanin FQ in the potentiation of prostaglandin cerebrovasoconstriction after brain injury [4].
• This interpretation is supported by the finding that adenosine- and CCPA-induced phosphorylation of ERK, JNK, and AKT are inhibited by pertussis toxin (inactivator of Gi proteins) and by DPCPX (A1-selective antagonist), but not by SCH58261, MRS1706, and VUF5574 (A2A-, A2B-, and A3-selective antagonists, respectively) [5].

High impact information on MAPK8

• LCAR, in contrast, prevents both gentamicin-induced Hrk up-regulation and apoptosis acting by means of c-Jun N-terminal kinase (JNK) [6].
• Therefore, we exposed endothelial cells to hydrogen peroxide (H(2)O(2)) and observed rapid activation of JNK within 15 min that involved phosphorylation of JNK and c-Jun and induction of AP-1 DNA binding activity [7].
• These data indicate that H(2)O(2)-induced JNK activation in endothelial cells involves the EGFR through an Src-dependent pathway that is distinct from EGFR ligand activation [7].
• Inhibition of protein kinase C and phosphoinositide 3-kinase did not effect JNK activation [7].
• In contrast, the tyrosine kinase inhibitors, genistein, herbimycin A, and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) significantly attenuated H(2)O(2)-induced JNK activation as did endothelial cell adenoviral transfection with a dominant-negative form of Src, implicating Src as an upstream activator of JNK [7].

Chemical compound and disease context of MAPK8

• In contrast, administration of SP 600125 (10(-6) and 10(-5) M) (JNK MAPK inhibitor) only attenuated brain injury induced U 46619 potentiation and such responses were significantly different than that in the presence of either U 0126 or SB 203580 after FPI [4].

Biological context of MAPK8

• JNK1/2, MKK4, c-Jun, and ATF-2 phosphorylation levels increase in response to TNFalpha and IL-1alpha treatment [8].
• The phenotypic properties of the endothelium are subject to modulation by oxidative stress, and the c-Jun N-terminal kinase (JNK) pathway is important in mediating cellular responses to stress, although activation of this pathway in endothelial cells has not been fully characterized [7].
• The JNK inhibitor SP-600125 (0.1 mM) significantly increased TER and resulted in COX-2 upregulation [9].
• Previous studies have shown that mitogen-activated protein kinases, such as extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK), mediate signal transduction from cell surface receptors to the nucleus and phosphorylate anti-apoptotic proteins thereby regulating programmed cell death [2].
• In porcine coronary arteries, short-term treatment with resveratrol (RSVL) substantially inhibited MAPK activity (IC50 = 37 microM); and immunoblot analyses revealed consistent reduction in the phosphorylation of ERK-1/-2, JNK-1 and p38, at active sites [10].

Anatomical context of MAPK8

• RESULTS: AT1 stimulation markedly increased expression of ERKs, JNK, p38 MAPK via Ca2+-dependent protein kinase C (PKC) isoforms (cPKC), as well as STATs 1, 3 and 5 in cultured porcine chromaffin cells [11].
• The level of phosphorylated c-Jun NH2-terminal kinase (JNK) in LLC-PK1 cells treated with CdCl2 increased after 30 min and remained elevated even at 8 hr [12].
• The present results showed that cadmium induces persistent activation of JNK pathway in a renal epithelial cell line, and that intracellular Ca2+ is necessary for the activation [12].
• Simultaneous measurement of ERK, p38, and JNK MAP kinase cascades in vascular smooth muscle cells [13].
• These results suggest that therapeutic intervention in the JNK signaling cascade, possibly by using CEP-1347, may offer opportunities to treat inner ear injuries [14].

Associations of MAPK8 with chemical compounds

• In contrast, activation of Jun-N-terminal kinase (JNK1) was sustained with U46619 but poorly induced by FGF-2 [15].
• The effects of PGE2 and forskolin on Cox-2 and phosphorylation of JNK1 were reversed with the protein kinase A inhibitor H89 [15].
• However, Ang II-induced JNK was not altered [16].
• The effect of JNK inhibitor 2 was evaluated [8].
• We therefore measured infarct size and p38, extracellular signal-regulated kinase (ERK), and c-Jun NH(2)-terminal kinase (JNK) MAPK phosphorylation (by biopsies) in enflurane-anesthetized pigs [3].

Other interactions of MAPK8

• However, activation of ERK2 by FGF-2 was not affected by PGE2 whereas that of JNK1 by U46619 was inhibited, suggesting that inhibition of COX-2 expression by cAMP may be downstream of ERK2 [15].
• When specific inhibitors of protein kinase A or Janus kinase are present, the lipolytic effect of IL-15 is attenuated (P < 0.01) [17].

Analytical, diagnostic and therapeutic context of MAPK8

• An inconsistent increase in p38, ERK, and p54 JNK phosphorylation (by Western blot) was found during IP; p46 JNK phosphorylation increased with the subsequent reperfusion [3].
• Activated ERK and JNK were assessed by determining phosphorylated ERK and JNK using immunoblotting in six normoxic (Nx) and 10 hypoxic (Hx) and five N-nitro-L-arginine (a NOS inhibitor, 40 mg/kg,) -pretreated hypoxic (N-nitro-L-arginine [NNLA]-Hx) 3-5 day old piglets [2].
• These results imply an involvement of Janus kinase/signal transducer and activator or transcription, MAP kinase and NOS-signaling pathways in the stimulatory effect of leptin on porcine somatotropes [18].
• Assignment of the porcine janus kinase 1 gene (JAK1) to chromosome 6q34-->q35 by fluorescence in situ hybridization and radiation hybrid mapping [19].
• By using phospho-specific c-Jun-N-terminal kinase (JNK) and c-Jun antibodies in immunohistochemistry, we show that the JNK pathway, associated with stress, injury, and apoptosis, is activated in hair cells after trauma [14].

References