Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development.
MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) are protein-serine/threonine kinases that are activated by ERK or p38 and phosphorylate eIF4E, which is involved in cap-dependent translation initiation. However, Mnk1/2 double knockout (Mnk-DKO) mice show normal cell growth and development despite an absence of eIF4E phosphorylation. Here we show that the tumorigenesis occurring in the Lck-Pten mouse model (referred to here as tPten(-/-) mice) can be suppressed by the loss of Mnk1/2. Phosphorylation of eIF4E was greatly enhanced in lymphomas of parental tPten(-/-) mice compared with lymphoid tissues of wild-type mice, but was totally absent in lymphomas of tPten(-/-); Mnk-DKO mice. Notably, stable knockdown of Mnk1 in the human glioma cell line U87MG resulted in dramatically decreased tumor formation when these cells were injected into athymic nude mice. Our data demonstrate an oncogenic role for Mnk1/2 in tumor development, and highlight these molecules as potential anticancer drug targets that could be inactivated with minimal side effects.
Ueda
Takeshi
T
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1.
Sasaki
Masato
M
Elia
Andrew J
AJ
Chio
Iok In Christine
II
Hamada
Koichi
K
Fukunaga
Rikiro
R
Mak
Tak W
TW
D000818:Animals; D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005910:Glioma / Q000473:pathology; D008223:Lymphoma / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000209:etiology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000502:physiology; D014183:Transplantation, Heterologous
D039561:Eukaryotic Initiation Factor-4E; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse