The PIM-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway

Michael Lilly, Jouko Sandholm, John J. Cooper, Päivi J. Koskinen, Andrew Kraft

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

We have examined potential mechanisms by which the Pim-1 kinase acts as a hematopoietic cell survival factor. Enforced expression of the wild type 33 kd (FD/hpim33) and 44 kd (FD/mpim44) Pim-1 proteins in murine factor-dependent FDCP1 cells prolonged survival after withdrawal of IL-3, while expression of a dominant negative Pim-1 protein (FD/pimNT81) shortened survival. Following removal of IL-3 FDCP1 cells exhibited loss of mitochondrial transmembrane potential and production of reactive oxygen species, as determined by flow cytometry analysis. The wild type Pim-1 proteins decreased these changes while the dominant negative protein enhanced mitochondrial dysfunction. The anti-apoptotic activity of the kinases could not be attributed to modulation of glutathione, catalase, or superoxide dismutase activities. Both the FD/hpim33 and FD/mpim44 cells maintained expression of bcl-2 mRNA following cytokine removal, while a substantial decrease was seen in FD/neo cells. To modulate Bcl-2 protein levels, a bcl-2 antisense RNA construct was coexpressed with the wild type pim-1 cDNAs. FD/hpim33 cells with low cellular Bcl-2 protein levels had shortened cytokine-independent survival compared with FD/hpim33 clones with high Bcl-2 expression. However survival of FD/mpim44 cells after IL-3 withdrawal was substantially independent of cellular Bcl-2 protein levels. The 33 kd protein delayed, and the 44 kd protein completely prevented enhanced cell death associated with enforced expression of human Bax protein however. Our results suggest that the 33 kd Pim-1 kinase may enhance cell survival through cooperation with and regulation of bcl-2. In addition the 44 kd kinase may regulate the expression or activity of other pro- and anti-apoptotic members of the bcl-2 family.

Original languageEnglish (US)
Pages (from-to)4022-4031
Number of pages10
JournalOncogene
Volume18
Issue number27
DOIs
StatePublished - Jul 8 1999
Externally publishedYes

Keywords

  • Apoptosis
  • FDCP1
  • IL-3
  • Mitochondria
  • bcl-2
  • pim-1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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