title: Rit-mediated stress resistance involves a p38-mitogen- and stress-activated protein kinase 1 (MSK1)-dependent cAMP response element-binding protein (CREB) activation cascade.
abstract: The cAMP response element (CRE)-binding protein (CREB) is a key regulatory factor of gene transcription, and plays an essential role in development of the central nervous system and for neuroprotection. Multiple signaling pathways have been shown to contribute to the regulation of CREB-dependent transcription, including both ERK and p38 mitogen-activated protein (MAP) kinases cascades. Recent studies have identified the Ras-related small G-protein, Rit, as a central regulator of a p38-MK2-HSP27 signaling cascade that functions as a critical survival mechanism for cells adapting to stress. Here, we examine the contribution of Rit-p38 signaling to the control of stress-dependent gene transcription. Using a pheochromocytoma cell model, we find that a novel Rit-p38-MSK1/2 pathway plays a critical role in stress-mediated CREB activation. RNAi-mediated Rit silencing, or inhibition of p38 or MSK1/2 kinases, was found to disrupt stress-mediated CREB-dependent transcription, resulting in increased cell death. Furthermore, ectopic expression of active Rit stimulates CREB-Ser133 phosphorylation, induces expression of the anti-apoptotic Bcl-2 and Bcl(XL) proteins, and promotes cell survival. These data indicate that the Rit-p38-MSK1/2 signaling pathway may have an important role in the stress-dependent regulation of CREB-dependent gene expression.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA. gshi2@uky.edu
authors.forename: Geng-Xian
authors.initials: GX
authors.lastname: Shi
authors.forename: Weikang
authors.initials: W
authors.lastname: Cai
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Andres
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C115634:RPS6KA4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; C486776:RIT1 protein, human; C472865:Rit1 protein, mouse; D018631:ras Proteins