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Chronic Lymphocytic Leukemia

Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells

Leukemia volume 21, pages 281–287 (2007)Cite this article

Abstract

Glucocorticoids induce apoptosis in chronic lymphocytic leukemia (CLL) cells through a caspase-dependent mechanism. However, their mechanism of action remains unknown. We have studied the regulation of the proapoptotic BH3-only Bcl-2 interacting mediator of cell death (BIM) in CLL cells. We demonstrate that glucocorticoids upregulate BIM at protein and mRNA levels. We have investigated the ability of different survival signals, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), stromal cell-derived factor-1α (SDF-1α), interleukin 4 (IL-4) and B-cell receptor (BCR) activation, to influence the levels of BIM and its induction by glucocorticoids. TPA downregulates BIMEL by extracellular signal-regulated kinase (ERK)-mediated BIM phosphorylation and further proteasome-mediated degradation. However, SDF-1α and BCR activation induce transient BIM phosphorylation, without protein degradation. Proteasome inhibitors do not modify the levels of BIM with respect to untreated cells. However, they induce apoptosis and inhibit TPA-induced BIMEL degradation, leading to its accumulation. In conclusion, the results implicate BIM in glucocorticoid-induced apoptosis in CLL cells. BIMEL phosphorylation through the ERK pathway targets the protein for proteasomal degradation.

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Acknowledgements

We thank Dr Clara Campás and Dr Esther Castaño for helpful discussions and suggestions, Dr Francesc Viñals for kindly providing the anti-ERK-1/2 antibody and Robin Rycroft and Lucille Banham for language assistance. We also thank the Unitat de Biologia and the Unitat de Genòmica from the Serveis Cientificotècnics at the Universitat de Barcelona for their technical support. DIS, AFS and AMC were recipients of a research fellowship from the Ministerio de Educación y Ciencia, MdF was the recipient of a fellowship from the AGAUR-Generalitat de Catalunya and LCM was the recipient of a fellowship from the José Carreras International Leukemia Foundation. This study was supported by a grant from the Ministerio de Educación y Ciencia and FEDER (SAF2004-00265) to JG.

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  1. J Gil and G Pons: These authors contributed equally to this work

Authors and Affiliations

  1. Departament de Ciències Fisiològiques II, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain

    D Iglesias-Serret, M de Frias, A F Santidrián, L Coll-Mulet, A M Cosialls, M Barragán, J Gil & G Pons

  2. Servei d'Hematologia, IDIBELL-Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain

    A Domingo

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  1. D Iglesias-Serret
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Correspondence to J Gil.

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Iglesias-Serret, D., de Frias, M., Santidrián, A. et al. Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. Leukemia 21, 281–287 (2007). https://doi.org/10.1038/sj.leu.2404483

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