Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation

Toshihiro Mochizuki, Chifumi Kitanaka, Kohji Noguchi, Akinori Sugiyama, Shigehide Kagaya, Shunji Chi, Akio Asai, Yoshiyuki Kuchino

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33 Citations (Scopus)

Abstract

Pim-1 oncoprotein is a serine/threonine kinase that can closely cooperate with c-Myc in lymphomagenesis, as does Bcl-2. Although the molecular mechanism of this cooperative transformation remains unknown, it is speculated that, similar to Bcl-2, Pim-1 contributes to transformation by inhibiting apoptosis. In this study, therefore, we examined the effect of Pim-1 expression on c-Myc-mediated apoptosis of Rat-1 fibroblasts triggered by serum deprivation. Our results showed that, rather than inhibiting apoptosis, Pim-1 expression stimulated c-Myc-mediated apoptosis in Rat-1 fibroblasts. Pim-1 stimulated c-Myc-mediated apoptosis through an enhancement of the c-Myc-mediated activation of caspase-3 (CPP32)-like proteases, since the suppression of this activity by a specific caspase inhibitor abolished the apoptosis stimulation by Pim-1. A kinase-defective Pim-1 mutant failed to stimulate c-Myc-mediated apoptosis, and Pim-1 expression alone in the absence of c-Myc overexpression did not induce apoptosis of serum-deprived Rat-1 cells, indicating that the kinase activity of Pim-1 and the activated c-Myc signaling pathway were required for apoptosis stimulation by Pim-1. Together, these results suggest that Pim-1 oncoprotein stimulates as a serine/threonine kinase the death signaling elicited by c-Myc at a step upstream of caspase-3-like protease activation in Rat-1 fibroblasts. Our results also suggest that Pim-1 kinase might function cooperatively with c-Myc through the phosphorylation of a factor(s) which regulates the common signaling pathway involved in c-Myc-mediated apoptosis and transformation.

Original languageEnglish
Pages (from-to)1471-1480
Number of pages10
JournalOncogene
Volume15
Issue number12
DOIs
Publication statusPublished - 1997

Keywords

  • Apoptosis
  • Caspase
  • Pim-1
  • Serine/threonine kinase
  • Transformation
  • c-Myc

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Mochizuki, T., Kitanaka, C., Noguchi, K., Sugiyama, A., Kagaya, S., Chi, S., Asai, A., & Kuchino, Y. (1997). Pim-1 kinase stimulates c-Myc-mediated death signaling upstream of caspase-3 (CPP32)-like protease activation. Oncogene, 15(12), 1471-1480. https://doi.org/10.1038/sj.onc.1201326