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

O&#39;Reilly, LA; Kruse, EA; Puthalakath, H; Kelly, PN; Kaufmann, T; Huang, DCS; Strasser, A

Author(s): O'Reilly, LA; Kruse, EA; Puthalakath, H; Kelly, PN; Kaufmann, T; Huang, DCS; Strasser, A;
Details: Publication Year 2009-07-01,Volume 183,Issue #1,Page 261-269
Journal Title: JOURNAL OF IMMUNOLOGY
Publication Type: Journal Article
Abstract: 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 Journal of Immunology, 2009, 183: 261-269.
Publisher: AMER ASSOC IMMUNOLOGISTS
Keywords: FAMILY-MEMBER BIM; BH3-ONLY PROTEIN BIM; BCL-2 FAMILY; CELL-SURVIVAL; INDUCED APOPTOSIS; SIGNALING PATHWAY; LYMPHOID-CELLS; KINASE PATHWAY; IMMUNE-SYSTEM; IN-VIVO
Publisher's Version: https://doi.org/10.4049/jimmunol.0803853
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Creation Date: 2009-07-01 12:00:00