The MKK(3/6)-p38-signaling cascade alters the subcellular distribution of hnRNP A1 and modulates alternative splicing regulation. Academic Article uri icon

Overview

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 MKK(3/6)-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.

publication date

  • April 17, 2000

Research

keywords

  • Alternative Splicing
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Gene Expression Regulation
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Mitogen-Activated Protein Kinase Kinases
  • Protein-Tyrosine Kinases
  • Ribonucleoproteins

Identity

PubMed Central ID

  • PMC2175157

Scopus Document Identifier

  • 0007570010

Digital Object Identifier (DOI)

  • 10.1083/jcb.149.2.307

PubMed ID

  • 10769024

Additional Document Info

volume

  • 149

issue

  • 2