The Mkk3/6-p38–Signaling Cascade Alters the Subcellular Distribution of Hnrnp A1 and Modulates Alternative Splicing Regulation
Open Access
- 17 April 2000
- journal article
- Published by Rockefeller University Press in The Journal of cell biology
- Vol. 149 (2), 307-316
- https://doi.org/10.1083/jcb.149.2.307
Abstract
Individual members of the serine-arginine (SR) and heterogeneous nuclear ribonucleoprotein (hnRNP) A/B families of proteins have antagonistic effects in regulating alternative splicing. Although hnRNP A1 accumulates predominantly in the nucleus, it shuttles continuously between the nucleus and the cytoplasm. Some but not all SR proteins also undergo nucleo-cytoplasmic shuttling, which is affected by phosphorylation of their serine/arginine (RS)–rich domain. The signaling mechanisms that control the subcellular localization of these proteins are unknown. We show that exposure of NIH-3T3 and SV-40 transformed green monkey kidney (COS) cells to stress stimuli such as osmotic shock or UVC irradiation, but not to mitogenic activators such as PDGF or EGF, results in a marked cytoplasmic accumulation of hnRNP A1, concomitant with an increase in its phosphorylation. These effects are mediated by the MKK3/6-p38 pathway, and moreover, p38 activation is necessary and sufficient for the induction of hnRNP A1 cytoplasmic accumulation. The stress-induced increase in the cytoplasmic levels of hnRNP A/B proteins and the concomitant decrease in their nuclear abundance are paralleled by changes in the alternative splicing pattern of an adenovirus E1A pre-mRNA splicing reporter. These results suggest the intriguing possibility that signaling mechanisms regulate pre-mRNA splicing in vivo by influencing the subcellular distribution of splicing factors.Keywords
This publication has 49 references indexed in Scilit:
- RNA splicing: What has phosphorylation got to do with it?Current Biology, 1999
- The Nuclear Cap-binding Complex Is a Novel Target of Growth Factor Receptor-coupled Signal TransductionPublished by Elsevier ,1999
- Functions of Ceramide in Coordinating Cellular Responses to StressScience, 1996
- Three paths to stress reliefNature, 1996
- MAPKs: new JNK expands the groupTrends in Biochemical Sciences, 1994
- Regulation of Alternative Splicing in Vivo by Overexpression of Antagonistic Splicing FactorsScience, 1994
- hnRNP PROTEINS AND THE BIOGENESIS OF mRNAAnnual Review of Biochemistry, 1993
- Shuttling of pre-mRNA binding proteins between nucleus and cytoplasmNature, 1992
- Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2Cell, 1992
- Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins.Genes & Development, 1988