ERK5 activates NF-kappaB in leukemic T cells and is essential for their growth in vivo.
MAPK cascades play a central role in the cellular response to the environment. The pathway involving the MAPK ERK5 mediates growth factor- and stress-induced intracellular signaling that controls proliferation or survival depending upon the cell context. In this study, we show that reducing ERK5 levels with a specific small hairpin RNA 5 (shERK5) reduced cell viability, sensitized cells to death receptor-induced apoptosis, and blocked the palliative effects of phorbol ester in anti-Fas Ab-treated cells. shERK5 decreased nuclear accumulation of the NF-kappaB p65 subunit, and conversely, ectopic activation of ERK5 led to constitutive nuclear localization of p65 and increased its ability to trans activate specific reporter genes. Finally, the T lymphoma cell line EL-4, upon expression of shERK5, proliferated in vitro, but failed to induce s.c. tumors in mice. Our results suggest that ERK5 is essential for survival of leukemic T cells in vivo, and thus represents a promising target for therapeutic intervention in this type of malignancy.
Garaude
Johan
J
Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 5535, IFR 122, 1919 Route de Mende, 34293 Montpellier, France.
Cherni
Seyma
S
Kaminski
Sandra
S
Delepine
Etienne
E
Chable-Bessia
Christine
C
Benkirane
Monsef
M
Borges
Joana
J
Pandiella
Atanasio
A
Iñiguez
Miguel Angel
MA
Fresno
Manuel
M
Hipskind
Robert A
RA
Villalba
Martin
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D049109:Cell Proliferation; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D047468:Immunoprecipitation; D019169:Jurkat Cells; D007938:Leukemia / Q000201:enzymology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport / Q000276:immunology; D034741:RNA, Small Interfering; D013601:T-Lymphocytes / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D019892:eIF-2 Kinase / Q000378:metabolism
D016328:NF-kappa B; D034741:RNA, Small Interfering; D019892:eIF-2 Kinase; D048054:Mitogen-Activated Protein Kinase 7