Lymphocyte transformation by Pim-2 is dependent on nuclear factor-kappaB activation.
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)-kappaB activation. Pim-2 activates NF-kappaB-dependent gene expression by inducing phosphorylation of the oncogenic serine/threonine kinase Cot, leading to both augmentation of IkappaB kinase activity and a shift in nuclear NF-kappaB from predominantly p50 homodimers to p50/p65 heterodimers. Blockade of NF-kappaB 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-kappaB blockade. The ability of Pim-2 to serve as an oncogene in vivo depends on sustained NF-kappaB activity. Thus, the transcriptional induction of Pim-2 initiates a novel NF-kappaB activation pathway that regulates cell survival.
Hammerman
Peter S
PS
Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Fox
Casey J
CJ
Cinalli
Ryan M
RM
Xu
Anne
A
Wagner
John D
JD
Lindsten
Tullia
T
Thompson
Craig B
CB
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*
D017931:DNA Primers; D020672:I-kappa B Proteins; D016328:NF-kappa B; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases