Loss of MNK function sensitizes fibroblasts to serum-withdrawal induced apoptosis.
Map kinase-interacting protein kinases 1 and 2 (MNK1, MNK2) function downstream of p38 and ERK MAP kinases, but there are large gaps in our knowledge of how MNKs are regulated and function. Mice deleted of both genes are apparently normal, suggesting that MNKs function in adaptive pathways during stress. Here, we show that mouse embryo fibroblasts (MEFs) obtained from mnk1 (-/-)/mnk2 (-/-) as well as mnk1 (-/-) and mnk2 (-/-) mice are sensitized to caspase-3 activation upon withdrawal of serum in comparison to wild-type cells. Caspase-3 cleavage occurs with all cells in the panel, but most rapidly and robustly in cells derived from mice lacking both MNK genes. Treatment of wild-type MEFs in the panel with a compound (CGP57380) that inhibits MNK1 and MNK2 sensitizes wild-type cells for serum-withdrawal induced apoptosis, suggesting that sensitization is due to loss of MNK function and not to a secondary event. Reintroduction of wild-type MNK1 in the double knockout MEFs results in decreased sensitivity to serum withdrawal that is not observed for wild-type MNK2, or the kinase dead variant. Our work identifies MNKs as kinases involved in anti-apoptotic signaling in response to serum withdrawal.
Chrestensen
Carol A
CA
Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
Eschenroeder
Andrew
A
Ross
William G
WG
Ueda
Takeshi
T
Watanabe-Fukunaga
Rie
R
Fukunaga
Rikiro
R
Sturgill
Thomas W
TW
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002469:Cell Separation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology*; D011687:Purines / Q000494:pharmacology
D000814:Aniline Compounds; D017304:Annexin A5; C466997:CGP 57380; D016895:Culture Media, Serum-Free; D011687:Purines; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases