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Published online 31 May 2005. doi:10.1083/jcb.200409099
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 169, Number 5, 755-763
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Article

 Cytokine-driven cell cycling is mediated through Cdc25A

Annette R. Khaled1,3, Dmitry V. Bulavin2, Christina Kittipatarin1, Wen Qing Li3, Michelle Alvarez1, Kyungjae Kim3,5, Howard A. Young4, Albert J. Fornace2, and Scott K. Durum3

1 University of Central Florida, BioMolecular Science Center, Orlando, FL 32628
2 Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892
3 Laboratory of Molecular Immunoregulation, National Cancer Institute at Frederick, Frederick, MD 21702
4 Laboratory of Experimental Immunology, National Cancer Institute at Frederick, Frederick, MD 21702
5 Department of Pharmacy, Sahm-Yook University, Seoul, Korea, 139-742

Correspondence to Annette R. Khaled: akhaled{at}mail.ucf.edu; or Scott K. Durum: durums{at}mail.ncifcrf.gov

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.

Abbreviations used in this paper: DP, dominant-positive; PI, propidium iodide; Rb, Retinoblastoma; RPA, RNase protection assay.


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