Elevated levels of oncogenic protein kinase Pim-1 induce the p53 pathway in cultured cells and correlate with increased Mdm2 in mantle cell lymphoma

Carol Hogan, Caroline Hutchison, Lynnette Marcar, Diane Milne, Mark Saville, John Goodlad, Neil Kernohan, David Meek

Research output: Contribution to journalArticlepeer-review

Abstract

Mutation of the p53 gene is a common event during tumor pathogenesis. Other mechanisms, such as mdm2 amplification, provide alternative routes through which dysfunction of the p53 pathway is promoted. Here, we address the hypothesis that elevated expression of pim oncogenes might suppress p53 by regulating Mdm2. At a physiological level, we show that endogenous Pim-1 and Pim-2 interact with endogenous Mdm2. Additionally, the Pim kinases phosphorylate Mdm2 in vitro and in cultured cells at Ser(166) and Ser(186), two previously identified targets of other signaling pathways, including Akt. Surprisingly, at high levels of Pim expression, as would occur in tumors, active, but not inactive, Pim-1 or Pim-2 blocks the degradation of both p53 and Mdm2 in a manner that is independent of Mdm2 phosphorylation, leading to increased p53 levels and, proportionately, p53-dependent transactivation. Additionally, Pim-1 induces endogenous ARF, p53, Mdm2, and p21 in primary murine embryo fibroblasts and stimulates senescence-associated beta-galactosidase levels, consistent with the induction of senescence. Immunohistochemical analysis of a cohort of 33 human mantle cell lymphomas shows that elevated expression of Pim-1 occurs in 42% of cases, with elevated Pim-2 occurring in 9% of cases, all of which also express Pim-1. Notably, elevated Pim-1 correlates with elevated Mdm2 in MCL with a p value of 0.003. Taken together, our data are consistent with the idea that Pim normally interacts with the p53 pathway but, when expressed at pathological levels, behaves as a classic dominant oncogene that stimulates a protective response through induction of the p53 pathway.

Original languageEnglish
Pages (from-to)18012-23
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number26
DOIs
Publication statusPublished - 27 Jun 2008

Keywords

  • Animals
  • Antigens, CD20
  • Cell Line, Tumor
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic
  • Genes, p53
  • Humans
  • Lymphoma, Mantle-Cell
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins c-pim-1
  • Transcriptional Activation
  • Transfection
  • Tumor Suppressor Protein p53

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