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Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts
Patricia Hess1, German Pihan, Charles L Sawyers
1Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA.
Abstract:
The c-Jun NH(2)-terminal kinase (JNK) is implicated in the apoptotic response of cells exposed to stress, but the JNK signal transduction pathway may not act exclusively in apoptosis. In some studies of tumor cells, JNK has been implicated in signaling cell survival. 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 vitro. 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.
Insights
The c-Jun NH(2)-terminal kinase (JNK) pathway, specifically Jnk1, is crucial for the survival of BCR-ABL-transformed B lymphoblasts. Disrupting Jnk1 impairs cell transformation and survival, highlighting its role in certain proliferative diseases.
Area of Science:
- Cellular signaling pathways
- Oncogenesis and cancer biology
- Hematopoietic stem cell biology
Background:
- The c-Jun NH(2)-terminal kinase (JNK) pathway is typically linked to apoptosis but can also mediate cell survival in tumor cells.
- The leukemogenic oncogene BCR-ABL activates JNK signaling in hematopoietic cells, promoting transformation.
- The precise role of JNK in BCR-ABL-mediated transformation and cell survival remains unclear.
Purpose of the Study:
- To investigate the role of the JNK signaling pathway, specifically Jnk1, in BCR-ABL-induced transformation and survival of pre-B cells.
- To determine if Jnk1 is required for the survival of transformed cells in the absence of stromal support.
- To elucidate the downstream mechanisms by which Jnk1 promotes cell survival.
Main Methods:
- Utilized knockout mice lacking the JNK ortholog Mapk8 (Jnk1).
- Assessed BCR-ABL-induced transformation of pre-B cells in vitro and in vivo.
- Analyzed the expression of survival-related genes, such as Bcl2, in Jnk1-deficient cells.
- Investigated the rescue effect of Bcl2 overexpression in Jnk1-deficient cells.
Main Results:
- Disruption of Jnk1 in mice led to defective in vitro and in vivo transformation of pre-B cells by BCR-ABL.
- Jnk1 protein was essential for the survival of BCR-ABL-transformed B lymphoblasts lacking stromal support.
- Jnk1 deficiency resulted in decreased expression of the anti-apoptotic protein Bcl2.
- Transgenic expression of Bcl2 rescued the survival defect in Jnk1-deficient cells.
Conclusions:
- Jnk1 acts as a critical signaling molecule for cell survival in BCR-ABL-transformed B lymphoblasts.
- Jnk1-mediated survival signaling is dependent on Bcl2 expression.
- The JNK pathway, through Jnk1, may contribute to the pathogenesis of proliferative diseases driven by BCR-ABL.