Cytokine-driven cell cycling is mediated through Cdc25A
Abbreviated Journal Title
J. Cell Biol.
S-PHASE CHECKPOINT; NF-KAPPA-B; INTRACELLULAR PH; MEMORY CELLS; T-CELLS; SURVIVAL; INTERLEUKIN-7; IL-7; PHOSPHORYLATION; PHOSPHATASE; Cell Biology
Lymphocytes are the central mediators of the immune response, requiring cytokines for survival and proliferation. Survival signaling targets the Bcl-2 family of apoptotic mediators, however, the pathway for the cytokine-driven proliferation of lymphocytes is poorly understood. Here we show that cytokine-induced cell cycle progression is not solely dependent on the synthesis of cyclin-dependent kinases (Cdks) or cyclins. Rather, we observe that in lymphocyte cell lines dependent on interleukin-3 or interleukin-7, or primary lymphocytes dependent on interleukin 7, the phosphatase Cdc25A is the critical mediator of proliferation. Withdrawal of IL-7 or IL-3 from dependent lymphocytes activates the stress kinase, p38 MAPK, which phosphorylates Cdc25A, inducing its degradation. As a result, Cdk/cyclin complexes remain phosphorylated and inactive and cells arrest before the induction of apoptosis. Inhibiting p38 MAPK or expressing a mutant Cdc25A, in which the two p38 MAPK target sites, S75 and S123, are altered, renders cells resistant to cytokine withdrawal, restoring the activity of Cdk/cyclin complexes and driving the cell cycle independent of a growth stimulus.
Journal of Cell Biology
"Cytokine-driven cell cycling is mediated through Cdc25A" (2005). Faculty Bibliography 2000s. 5341.