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Survival signaling mediated by c-Jun NH2-terminal kinase in transformed B lymphoblasts

Nature Genetics volume 32, pages 201–205 (2002)Cite this article

Abstract

The c-Jun NH2-terminal kinase (JNK) is implicated in the apoptotic response of cells exposed to stress1, but the JNK signal transduction pathway may not act exclusively in apoptosis1. In some studies of tumor cells, JNK has been implicated in signaling cell survival1. The possibility that JNK might mediate a survival signal in tumor cells is consistent with the observation that it is activated in response to some oncogenes, such as the leukemogenic oncogene BCR–ABL, which is created by a reciprocal translocation between human chromosomes 9 and 22 (ref. 2). The BCR-ABL protein activates the JNK signaling pathway in hematopoietic cells and increases transcriptional activity mediated by the transcription factor AP1 (ref. 3). Also, inhibition of c-Jun or JNK prevents BCR–ABL-induced cell transformation in vitro3,4. Although this implicates the JNK signaling pathway in transformation by BCR–ABL, the possible role of JNK in this process is unclear. We find that disruption of the JNK ortholog Mapk8 (also known as Jnk1) in mice causes defective transformation of pre-B cells by BCR–ABL in vitro and in vivo. The Jnk1 protein is required for the survival of the transformed cells in the absence of stromal support. Failure to survive is associated with decreased expression of Bcl2, and the effect of Jnk1 deficiency can be rescued by transgenic expression of Bcl2. Our results show that Jnk1 signals cell survival in transformed B lymphoblasts and suggest that it may contribute to the pathogenesis of some proliferative diseases.

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Figure 1: Jnk1 is required for efficient transformation by BCR–ABL in vitro.
Figure 2: Jnk1 is not required for bone marrow disease caused by BCR–ABL, but is required for efficient infiltration of peripheral organs.
Figure 3: Jnk1 deficiency causes decreased expression of Bcl2.
Figure 4: Transgenic expression of Bcl2 restores BCR–ABL-induced disease in Jnk1-deficient mice.

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Acknowledgements

We thank M. Roussel for providing the MSCV vector, L. Boxer for the Bcl2 promoter reporter plasmid, R. Hulspas for assistance with FACS analysis, J. Wu and Q. Liu for statistical analysis, I. Joris for histological examination, Y. Liu for preparing slides, T. Barrett, J. Brackett and S. Stone for technical assistance, and K. Gemme for administrative assistance. R.J.D., C.L.S. and R.A.F. are investigators of the Howard Hughes Medical Institute. This study was supported in part by a research grant from the US National Cancer Institute and by a center grant from the US National Institutes of Health.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, 01605, Massachusetts, USA

    Patricia Hess & Roger J. Davis

  2. Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    German Pihan

  3. Howard Hughes Medical Institute and Department of Medicine, University of California, Los Angeles, California, USA

    Charles L. Sawyers

  4. Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

    Richard A. Flavell

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Correspondence to Roger J. Davis.

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Hess, P., Pihan, G., Sawyers, C. et al. Survival signaling mediated by c-Jun NH2-terminal kinase in transformed B lymphoblasts. Nat Genet 32, 201–205 (2002). https://doi.org/10.1038/ng946

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