No abstract

Cell response to a wide variety of extracellular signals is mediated by either mitogenic activation of the Raf/ MEK/ERK kinase cascade or stress-induced activation of the mitogen-activated protein kinase (MAPK) family members c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) or p38. We have examined communications between these stress-and mitogen-induced signaling pathways.We show here that the stress cascade activator arsenite activates extracellular signal-regulated kinase (ERK) in addition to p38 albeit with different kinetics. Whereas p38 is an early response kinase, ERK activation occurs with delayed time kinetics at 2-4 h. We observed activation of ERK upon arsenite treatment in many different cell lines. ERK activation is strongly enhanced by overexpression of p38 and mitogen-activated protein kinase kinase 6 (MKK6) but is blocked by dominant negative kinase versions of p38 and MKK6 or the specific p38 inhibitor SB203580. Arsenite-induced ERK activation is mediated by Ras, Raf, and MEK but appears to be independent of de novo protein synthesis. These data provide the first evidence for a p38 dependent activation of the mitogenic kinase cascade in stress-stimulated cells.

ARF , which was encoded by the Cdkn2a/INK4A locus. Thus, 3pK is a candidate regulator of phosphorylation-dependent PcG/chromatin interaction. We speculate that phosphorylation may not only affect chromatin association but, in addition, the function of individual complex members. Our findings linked for the first time MAPK signaling pathways to the Polycomb transcriptional memory system. This suggests a novel mechanism by which a silenced gene status can be modulated and implicates PcGmediated repression as a dynamically controlled process.

Extracellular signal regulated kinase 5 (ERK5) is a novel member of the mitogen-activated protein kinase (MAPK) family with a poorly defined physiological function. Since ERK5 and its upstream activator MEK5 are abundant in skeletal muscle we examined a function of the cascade during muscle differentiation. We show that ERK5 is activated upon induction of differentiation in mouse myoblasts and that selective activation of the pathway results in promoter activation of differentiation-specific genes. Moreover, myogenic differentiation is completely blocked when ERK5 expression is inhibited by antisense RNA. Thus, we conclude that the MEK5/ERK5 MAP kinase cascade is critical for early steps of muscle cell differentiation.

Tumor necrosis factor a (TNF-alpha) is a potent proinflammatory cytokine and plays a crucial role in early events of inflammation. TNF-alpha is primarily produced by monocytes and T lymphocytes. In particular, T-cell-derived TNF-alpha plays a critical role in autoimmune inflammation and superantigen-induced septic shock. However, little is known about the intracellular signaling pathways that regulate TNF expression in T cells. Here we show that extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38-mitogen-activated protein kinase (MAPK) pathways control the transcription and synthesis of TNF-alpha in A3.01 T cells that produce the cytokine upon T cell activation by costimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) and ionomycin. Selective activation of each of the distinct MAPK pathways by expression of constitutively active kinases is sufficient for TNF-alpha promoter induction. Furthermore, blockage of all three pathways almost abolishes TPA/ionomycin-induced transcriptional activation of the TNF-alpha promoter. Selective inhibition of one or more MAPK pathways impairs TNF-alpha induction by TPA/ionomycin, indicating a cooperation between these signal transduction pathways. Our approach revealed that the MAPK kinase 6 (MKK6)/p38 pathway is involved in both transcriptional and posttranscriptional regulation of TNF expression. Moreover, analysis of the progressive 5' deletion mutants of the TNF-alpha promoter indicates that distinct promoter regions are targeted by either ERK-, JNK-, or p38-activating pathways. Thus, unlike what has been reported for other TNF-alpha-producing cells, all three MAPK pathways are critical and cooperate to regulate transcription of the TNF-alpha gene in T lymphocytes, suggesting a T-cell-specific regulation of the cytokine.