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.
ERK5 activates NF-kappaB in leukemic T cells and is essential for their growth in vivo
Garaude, J.; Cherni, S.; Kaminski, S.; Delepine, E.; Chable-Bessia, C.; Benkirane, M.; Borges, J.; Pandiella, A.; Iniguez, M. A.; Fresno, M.; Hipskind, R. A.; Villalba, M.
2006-12-01 / vol 177 / pages 7607-17
Humans; Animals; Mice; Immunoprecipitation; Blotting, Western; Electrophoresis, Polyacrylamide Gel; *Cell Proliferation; RNA, Small Interfering; Transfection; Lymphocyte Activation/immunology; Apoptosis/physiology; Mitogen-Activated Protein Kinase 7/*metabolism; Jurkat Cells; Trans-Activation (Genetics); eIF-2 Kinase/metabolism; Leukemia/*enzymology; NF-kappa B/*metabolism; Protein Transport/immunology; T-Lymphocytes/*metabolism