Cross-talk between the p38 alpha and JNK MAPK Pathways Mediated by MAP Kinase Phosphatase-1 Determines Cellular Sensitivity to UV Radiation

TY - JOUR

T1 - Cross-talk between the p38 alpha and JNK MAPK Pathways Mediated by MAP Kinase Phosphatase-1 Determines Cellular Sensitivity to UV Radiation

AU - Staples, Christopher J.

AU - Owens, David M.

AU - Maier, Jana V.

AU - Cato, Andrew C. B.

AU - Keyse, Stephen M.

PY - 2010/8/20

Y1 - 2010/8/20

N2 - 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 p38 alpha 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 p38 alpha-dependent DUSP1/MKP-1 transcription. Dusp1/Mkp-1 null MEFs display increased signaling through both the p38 alpha 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 p38 alpha 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 p38 alpha and JNK pathways mediated by induction of DUSP1/MKP-1 regulates the cellular response to UV radiation.

AB - 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 p38 alpha 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 p38 alpha-dependent DUSP1/MKP-1 transcription. Dusp1/Mkp-1 null MEFs display increased signaling through both the p38 alpha 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 p38 alpha 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 p38 alpha and JNK pathways mediated by induction of DUSP1/MKP-1 regulates the cellular response to UV radiation.

KW - SIGNAL-TRANSDUCTION PATHWAY

KW - INNATE IMMUNE-RESPONSES

KW - C-FOS

KW - TRANSCRIPTIONAL ACTIVATION

KW - DIFFERENTIAL REGULATION

KW - CISPLATIN RESISTANCE

KW - FEEDBACK-REGULATION

KW - INDUCED APOPTOSIS

KW - GENOTOXIC STRESS

KW - GENE-EXPRESSION

UR - https://www.scopus.com/pages/publications/77956200392

U2 - 10.1074/jbc.M110.117911

DO - 10.1074/jbc.M110.117911

M3 - Article

C2 - 20547488

SN - 0021-9258

VL - 285

SP - 25928

EP - 25940

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 34

ER -