p38 MAPK and JNK Phosphorylate and modulate GR Transcriptional Activity

LORENA FRANCO, MONICA COSTAS AND OMAR COSO

Cataratas del Iguazu

Congreso; Gene Expression and RNA Processing; 2003

The glucocorticoid receptor (GR) is a steroid hormone receptor known to regulate, erther directly or indirectly, target genes involved in cell differentiation, thymocyte selection, lung rnaturatlon, bone turnover, glucose homeostasis and inflammation. Steroid hormones are the primary signal for activating the receptor's transcriptional regulatory fundlons This transcriptional activation can be also modulated both postlvely and negatively by phosphorylation. GR is phosphorylated in its N-terminal transcriptional regulatory region, by the cyclin-dependent kinase (Cdk) and the mytogen-activated protein kineses (MAPKs). The best known members of MAPK family are Extracellular-signal Regulated Kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK. The objective of the present study was to investigate the role of MAPKs in the regulation of GR transactivation activity. Co-lmmunoprecipitation assays demonstrated physical interacfions between GR and p38, ERK2 and JNK. GR was target of phosphorylation by p38, ERK2 and JNK by In vitro kinase assays. p38 and GR coiocaiized in the nucleus of L-929 cells stimulated with TNF-α and Dexamethasone (Dex) by confocal microscopy and GR irnrnunoblots of subcellular fractions. GR transcriptional activation was promoted by a p38 kinase activator, MKK6, in L-929 transfected cells. While JNK kinase activator, MLK3, diminished it. GR transactivation activity was abrogated in the presence of p38 specific inhibitor S8203580. These data suggests that p38. JNK and ERK interact with GR, induce its phosphorylation, but differently modulate its transcriptional activity: p38 upregulates it and JNK diminishes it. This work opens new perspectives in the study of crosstalks between the signal transduction pathways that regulate GR with p38 and JNK, which might be relevant in diverse biological systems.