Cross-talk between the p38α and JNK MAPK Pathways Mediated by MAP Kinase Phosphatase-1 Determines Cellular Sensitivity to UV Radiation

Abstract

MAPK phosphatase-1 (DUSP1/MKP-1) is a mitogen and stress-inducible dual specificity protein phosphatase, which can inactivate all three major classes of MAPK in mammalian cells. DUSP1/MKP-1 is implicated in cellular protection against a variety of genotoxic insults including hydrogen peroxide, ionizing radiation, and cisplatin, but its role in the interplay between different MAPK pathways in determining cell death and survival is not fully understood. We have used pharmacological and genetic tools to demonstrate that DUSP1/MKP-1 is an essential non-redundant regulator of UV-induced cell death in mouse embryo fibroblasts (MEFs). The induction of DUSP1/MKP-1 mRNA and protein in response to UV radiation is mediated by activation of the p38α but not the JNK1 or JNK2 MAPK pathways. Furthermore, we identify MSK1 and -2 and their downstream effectors cAMP-response element-binding protein/ATF1 as mediators of UV-induced p38α-dependent DUSP1/MKP-1 transcription. Dusp1/Mkp-1 null MEFs display increased signaling through both the p38α and JNK MAPK pathways and are acutely sensitive to UV-induced apoptosis. This lethality is rescued by the reintroduction of wild-type DUSP1/MKP-1 and by a mutant of DUSP1/MKP-1, which is unable to bind to either p38α or ERK1/2, but retains full activity toward JNK. Importantly, whereas small interfering RNA-mediated knockdown of DUSP1/MKP-1 sensitizes wild-type MEFs to UV radiation, DUSP1/MKP-1 knockdown in MEFS lacking JNK1 and -2 does not result in increased cell death. Our results demonstrate that cross-talk between the p38α and JNK pathways mediated by induction of DUSP1/MKP-1 regulates the cellular response to UV radiation.

Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways

“…In response to cellular damage induced by, for example, UV, crosstalk occurs between the p38α and JNK pathways that is precisely regulated by MAPK phosphatase-1 (DUSP1/MKP-1), and the lack of this phosphatase strongly sensitizes mouse embryonic fibroblasts (MEFs) to UV-induced apoptosis [43]. In addition and interestingly, during the neurodegeneration of rat cortical neurons induced by the…”

p38 MAPK mediates calcium oxalate crystal-induced tight junction disruption in distal renal tubular epithelial cells

“…p38 is a member of MAPK pathway and can be activated by several stimuli, especially extracellular stresses111213. The activated form of p38 MAPK is phosphorylated p38 MAPK38.…”

“…p38 MAPK is one of signaling proteins in MAPK pathway that can be activated by various extracellular stresses, e.g., UV radiation11, hydrogen peroxide12, and proinflammatory cytokines13. Interestingly, p38 MAPK also plays role in modulation of tight junction function by regulating expression of tight junction proteins in response to several stimuli.…”

Ziram activates mitogen-activated protein kinases and decreases cytolytic protein levels in human natural killer cells

“…The stability of the more moderate activation seen at 2.5 µM may be due to that fact that this level of activation doesn’t cause as robust an activation of this turn-off mechanism . It has been shown (in other mammalian cells) that activation of p38 induces the production of MAPK phosphatase-1 (Staples et al, 2010) which is capable of dephosphorylating and thus inactivating both p44/42 and p38 MAPKs (Dickinson and Keyse, 2006). It is possible that such a p38 induced activation of an MKP-1 may be occurring in NK cells and is an area for further study.…”