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Lymphocyte Transformation by Pim-2 Is Dependent on Nuclear Factor-B Activation

¹ Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania; and ² Department of Biology, Haverford College, Haverford, Pennsylvania

Pim-2 is a transcriptionally regulated oncogenic kinase that promotes cell survival in response to a wide variety of proliferative signals. Deregulation of Pim-2 expression has been documented in several human malignancies, including leukemia, lymphoma, and multiple myeloma. Here, we show that the ability of Pim-2 to promote survival of cells is dependent on nuclear factor (NF)-B activation. Pim-2 activates NF-B–dependent gene expression by inducing phosphorylation of the oncogenic serine/threonine kinase Cot, leading to both augmentation of IB kinase activity and a shift in nuclear NF-B from predominantly p50 homodimers to p50/p65 heterodimers. Blockade of NF-B function eliminates Pim-2–mediated survival in both cell lines and primary cells, and both Cot phosphorylation and expression are required for the prosurvival effects of Pim-2. Although Pim-2 cooperates with Myc to promote growth factor-independent cell proliferation, this feature is abrogated by NF-B blockade. The ability of Pim-2 to serve as an oncogene in vivo depends on sustained NF-B activity. Thus, the transcriptional induction of Pim-2 initiates a novel NF-B activation pathway that regulates cell survival.

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