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J. Biol. Chem., Vol. 283, Issue 26, 18012-18023, June 27, 2008

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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, and David Meek¹

From the Biomedical Research Centre, Division of Pathology and Neuroscience, ^¶Maternal and Child Health Sciences, and ^||Division of Surgery and Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom

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 Ser¹⁶⁶ and Ser¹⁸⁶, 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 β-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.

Received for publication, November 27, 2007 , and in revised form, April 11, 2008.

^* This work was supported by Cancer Research UK, the Association for International Cancer Research, and the Biomedical Research Centre, Dundee. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–6.

¹ To whom correspondence should be addressed: Biomedical Research Centre, Ninewells Hospital, Level 5, Dundee DD1 9SY, United Kingdom. Fax: 44-1382-669993; E-mail: d.w.meek{at}dundee.ac.uk.

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