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[摘要]：Elevated levels of reactive oxygen species (ROS) are found in most oncogenically transformed cells and are proposed to promote cellular transformation through mechanisms such as inhibition of phosphatases. BCR-ABL, the oncoprotein associated with the majority of chronic myeloid leukemias (CMLs), induces accumulation of intracellular ROS, causing enhanced signaling down-stream of PI3K. Previously we have shown that the transcription factor nuclear factor-kappa B (NF-kappa B) is activated by BCR-ABL expression and is required for BCR-ABL-mediated cellular transformation. Inhibition of I kappa B kinase (IKK beta) and NF-kappa B leads to cell death through an unknown mechanism. Here, we analyze the potential involvement of NF-kappa B in moderating BCR-ABL-induced ROS levels to protect from death. The data confirm that BCR-ABL promotes ROS and demonstrate that NF-kappa B prevents excessive levels. Inhibition of NF-kappa B leads to an increase in ROS levels and to cell death, which is at least partially controlled through ROS-induced c-Jun N-terminal kinase activity. The data demonstrate that one function for NF-kappa B in oncogenesis is the suppression of oncoprotein-induced ROS levels and that inhibition of NF-jB in some cancers, including CML, will increase ROS levels and promote cell death. Oncogene (2011) 30, 4557-4566; doi: 10.1038/onc.2011.156; published online 30 May 2011 |
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