Authors

A. R. Khaled; D. V. Bulavin; C. Kittipatarin; W. Q. Li; M. Alvarez; K. Kim; H. A. Young; A. J. Fornace;S. K. Durum

Comments

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Abbreviated Journal Title

J. Cell Biol.

Keywords

S-PHASE CHECKPOINT; NF-KAPPA-B; INTRACELLULAR PH; MEMORY CELLS; T-CELLS; SURVIVAL; INTERLEUKIN-7; IL-7; PHOSPHORYLATION; PHOSPHATASE; Cell Biology

Abstract

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 Title

Journal of Cell Biology

Volume

169

Issue/Number

5

Publication Date

1-1-2005

Document Type

Article

Language

English

First Page

755

Last Page

763

WOS Identifier

WOS:000229600100010

ISSN

0021-9525

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