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MEK/ERK-Mediated Phosphorylation of Bim Is Required to Ensure Survival of T and B Lymphocytes during Mitogenic Stimulation

Lorraine A. O'Reilly^*, Elizabeth A. Kruse^*,, Hamsa Puthalakath^1,*, Priscilla N. Kelly^*, Thomas Kaufmann^2,*, David C. S. Huang^* and Andreas Strasser^3,*

^* Water and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia; and Department of Medical Biology, Melbourne University, Melbourne, Victoria, Australia

Survival and death of lymphocytes are regulated by the balance between pro- and antiapoptotic members of the Bcl-2 family; this is coordinated with the control of cell cycling and differentiation. Bim, a proapoptotic BH3-only member of the Bcl-2 family, can be regulated by MEK/ERK-mediated phosphorylation, which affects its binding to pro–survival Bcl-2 family members and its turnover. We investigated Bim modifications in mouse B and T lymphoid cells after exposure to apoptotic stimuli and during mitogenic activation. Treatment with ionomycin or cytokine withdrawal caused an elevation in Bim_EL, the most abundant Bim isoform. In contrast, in mitogenically stimulated T and B cells, Bim_EL was rapidly phosphorylated, and its levels declined. Pharmacological inhibitors of MEK/ERK signaling prevented both of these changes in Bim, reduced proliferation, and triggered apoptosis of mitogen-stimulated T and B cells. Loss of Bim prevented this cell killing but did not restore cell cycling. These results show that during mitogenic stimulation of T and B lymphocytes MEK/ERK signaling is critical for two distinct processes, cell survival, mediated (at least in part) through phosphorylation and consequent inhibition of Bim, and cell cycling, which proceeds independently of Bim inactivation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: La Trobe University, Bundoora, Victoria, Australia.

² Current address: Institute of Pharmacology, University of Bern, Bern, Switzerland.

³ Address correspondence and reprint requests to Dr. Andreas Strasser, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia. E-mail address: strasser{at}wehi.edu.au

⁴ Abbreviations used in this paper: PI, propidium iodide; -PPase, -phosphatase; HSP70, heat shock protein 70; wt, wild type.

⁵ The online version of this article contains supplemental material.