Cytokine-driven cell cycling is mediated through Cdc25A.
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.
Khaled
Annette R
AR
University of Central Florida, BioMolecular Science Center, Orlando, FL 32628, USA. akhaled@mail.ucf.edu
Bulavin
Dmitry V
DV
Kittipatarin
Christina
C
Li
Wen Qing
WQ
Alvarez
Michelle
M
Kim
Kyungjae
K
Young
Howard A
HA
Fornace
Albert J
AJ
Durum
Scott K
SK
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020134:Catalytic Domain / Q000502:physiology; D018797:Cell Cycle Proteins / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D007109:Immunity / Q000276:immunology*; D007377:Interleukin-3 / Q000276:immunology / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology; D013312:Stress, Physiological / Q000276:immunology / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018797:Cell Cycle Proteins; D016207:Cytokines; D007377:Interleukin-3; D015851:Interleukin-7; D048051:p38 Mitogen-Activated Protein Kinases; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases