PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence.
Oncogenic ras activates multiple signaling pathways to enforce cell proliferation in tumor cells. The ERK1/2 mitogen-activated protein kinase pathway is required for the transforming effects of ras, and its activation is often sufficient to convey mitogenic stimulation. However, in some settings oncogenic ras triggers a permanent cell cycle arrest with features of cellular senescence. How the Ras/ERK1/2 pathway activates different cellular programs is not well understood. Here we show that ERK1/2 localize predominantly in the cytoplasm during ras-induced senescence. This cytoplasmic localization seems to be dependent on an active nuclear export mechanism and can be rescued by the viral oncoprotein E1A. Consistent with this hypothesis, we showed that E1A dramatically down-regulated the expression of the ERK1/2 nuclear export factor PEA-15. Also, RNA interference against PEA-15 restored the nuclear localization of phospho-ERK1/2 in Ras-expressing primary murine embryo fibroblasts and stimulated their escape from senescence. Because senescence prevents the transforming effect of oncogenic ras, our results suggest a tumor suppressor function for PEA-15 that operates by means of controlling the localization of phospho-ERK1/2.
Université de Montréal, Département de Biochimie, Montréal, Québec H3C 3J7, Canada.
Marie-France
MF
Gaumont-Leclerc
Uptal Kumar
UK
Mukhopadhyay
Stéphane
S
Goumard
Gerardo
G
Ferbeyre
D021581:Active Transport, Cell Nucleus; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D020935:MAP Kinase Signaling System; D051379:Mice; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008938:Mitosis; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D034622:RNA Interference; D012190:Retroviridae / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D051017:Apoptosis Regulatory Proteins; D005231:Fatty Acids, Unsaturated; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins; D001973:Bromodeoxyuridine; C038753:leptomycin B