Journal
JOURNAL OF CELL BIOLOGY
Volume 149, Issue 2, Pages 307-316Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.149.2.307
Keywords
alternative splicing; hnRNP A1; signal transduction; p38 kinase; stress signaling
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Funding
- Medical Research Council [MC_U127584479] Funding Source: researchfish
- MRC [MC_U127584479] Funding Source: UKRI
- Medical Research Council [MC_U127584479] Funding Source: Medline
- NCI NIH HHS [CA13106] Funding Source: Medline
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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 Al 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 Al, 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 Al 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.
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