p38 MAP-Kinases pathway regulation, function and role in human diseases

Abstract

Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38alpha, p38beta, p38gamma and p38delta) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.

Gene expression in histologically normal epithelium from breast cancer patients and from cancer-free prophylactic mastectomy patients shares a similar profile

“…Thus, MAPK pathway deregulation may be implicated early in breast cancer development, and may differentiate PM from HN epithelium. The MAPK functions in cell cycle and transcriptional regulation and in the immune response may thus inhibit tumourigenesis (Bradham and McClay, 2006;Cuenda and Rousseau, 2007), Therefore, it is not surprising to see a higher expression of genes in this pathway in NlEpi from women without breast cancer (RM and perhaps PM samples). Alternatively, a FOS JUN BAG5 PTG2 CD93 CLU IER3 AHNAK BAG5 FOS FRZB IER3 IF16 IL6 JUN KLF4 ZFP36 YVVHAZ TXNIP TNC SPRY1 SNF1LK SEMA5A PTGS2 PRDX2 NR4A2 NR4A1 MCL1 MARCKS MAFF FRZB IER3 IFI6 IL6 JUN KLF4 MAFF MCL1 NR4A1 NR4A2 NR4A3 ZFP36 YWHAZ YWHAZ SAV1 PRDX2 NR4A1 MCL1 IL6 IFI6 TXNIP TRO TNC SPRY1 SNF1LK SEMA5A PTP4A1 PTGS2 PRDX2 AHNAK ABLIM1 BAG5 BST2 BTG2 CLU EGR1 ETS2 FHL1 FOS FOSB Figure 4 Gene list analysis.…”

Heat stress upregulates chaperone heat shock protein 70 and antioxidant manganese superoxide dismutase through reactive oxygen species (ROS), p38MAPK, and Akt

“…Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses, both acute and chronic (Cuenda and Rousseau 2007;Johnson and Lapadat 2002). As p38MAPK activity is critical for normal immune and inflammatory responses, different components of this pathway have become potential targets for the treatment of autoimmune and inflammatory diseases .…”

The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis

“…Particularly, a recent study showed the role of p38 MAPK as a tumor suppressor. 29 This involves promoting cell growth arrest and inducing cell apoptosis. 30 Bortezomib-mediated induction of apoptosis in leukemia cells has been linked to JNK and p38MAPK activation.…”