Up-regulation of c-jun mRNA in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-Jun N-terminal kinases are required for efficient up-regulation of c-Jun protein

Abstract

Cardiac hypertrophy, an important adaptational response, is associated with up-regulation of the immediate early gene, c-jun, which encodes the c-Jun transcription factor. c-Jun may feed back to up-regulate its own transcription and, since the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein kinases (MAPKs) phosphorylate c-Jun(Ser-63/73) to increase its transactivating activity, JNKs are thought to be the principal factors involved in c-jun up-regulation. Hypertrophy in primary cultures of cardiac myocytes is induced by endothelin-1, phenylephrine or PMA, probably through activation of one or more of the MAPK family. These three agonists increased c-jun mRNA with the rank order of potency of PMAendothelin-1> phenylephrine. Up-regulation of c-jun mRNA by endothelin-1 was attenuated by inhibitors of protein kinase C (GF109203X) and the extracellular signal-regulated kinase (ERK) cascade (PD98059 or U0126), but not by inhibitors of the JNK (SP600125) or p38-MAPK (SB203580) cascades. Hyperosmotic shock (0.5M sorbitol) powerfully activates JNKs, but did not increase c-jun mRNA. These data suggest that ERKs, rather than JNKs, are required for c-jun up-regulation. However, endothelin-1 and phenylephrine induced greater up-regulation of c-Jun protein than PMA and phosphorylation of c-Jun(Ser-63/73) correlated with the level of c-Jun protein. Up-regulation of c-Jun protein by endothelin-1 was attenuated by inhibitors of protein kinase C and the ERK cascade, probably correlating with a primary input of ERKs into transcription. In addition, SP600125 inhibited the phosphorylation of c-Jun(Ser-63/73), attenuated the increase in c-Jun protein induced by endothelin-1 and increased the rate of c-Jun degradation. Thus whereas ERKs are the principal MAPKs required for c-jun transcription, JNKs are necessary to stabilize c-Jun for efficient up-regulation of the protein.

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“…HEK 293 cells lines stably overexpressing the FLAGtagged ␤ 2 AR-GFP were cultured as described (22). Preparation and short-term culture of neonatal rat ventricular myocytes were as described (23,24), where 24 h after plating they were placed in low-serum medium.…”

Interaction of Neisseria meningitidis with human brain microvascular endothelial cells: role of MAP- and tyrosine kinases in invasion and inflammatory cytokine release

“…The anthrapyrazolone SP600125 has recently been characterized by Bennett et al (2001) as a novel inhibitor of JNK catalytic activity. This compound inhibits JNK1, JNK2 and JNK3 with a high specificity (IC 50 : 0.04-0.09 mM) and several laboratories have used this inhibitor to characterize the role of JNK in several cellular processes (Clerk et al, 2002;Shin et al, 2002;Hashimoto et al, 2003;Besirli and Johnson, 2003). SP600125 has been tested on different kinases, including MAPKs ERK and p38 and the serine threonine kinase PKA (Bennett et al, 2001), and has been found to have no in vitro inhibitory effects on the activities of these kinases in the concentration we used.…”

c-Jun N-terminal kinase is required for vitamin E succinate-induced apoptosis in human gastric cancer cells

“…Activated JNK in turn could phosphorylate transcription factors, c-Jun and ATF-2, which are components of the dimeric activating protein (AP)-1 [49][50][51] . Here, we determined the expression of phospho-JNK and JNK in VES-stimulated SGC-7901 cells.…”