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© The Rockefeller University Press,
0021-9525/2000//307 $5.00
The Journal of Cell Biology, Volume 149, Number 2,
, 2000 307-316
Original Article |
The Mkk3/6-p38–Signaling Cascade Alters the Subcellular Distribution of Hnrnp A1 and Modulates Alternative Splicing Regulation
javier.caceres{at}hgu.mrc.ac.uk
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.
Key Words: alternative splicing • hnRNP A1 • signal transduction • p38 kinase • stress signaling
© 2000 The Rockefeller University Press
Abbreviations used in this paper: ActD, actinomycin D; CBC, nuclear cap-binding complex; COS, SV-40 transformed green monkey kidney; ERK, extracellular signal regulated kinase; hnRNP, heterogeneous nuclear ribonucleoprotein; JNK, jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK-1 kinase; MKK, MAP-kinase kinase; OSM, osmotic shock; PKA, protein kinase A; RS, arginine/serine; SAPK, stress-activated protein kinase; SR, serine-arginine.
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