Pim kinase-dependent inhibition of c-Myc degradation.

Abstract

Pim kinases are found to be highly expressed in leukemia, lymphoma, prostate and pancreatic cancer. Bitransgenic mice overexpressing either Pim-1 or Pim-2 and c-Myc succumb to pre-B-cell lymphoma at a strikingly accelerated speed. Despite that Pim-1/Pim-2 has long been recognized as a strong synergistic partner with c-Myc in tumorigenesis, the mechanism underlying the synergism is still not well understood. Overexpression of Pim-1/Pim-2 kinase dramatically stabilizes c-Myc in vivo, and the stabilization is partially mediated by phosphorylation of c-Myc by Pim kinase on a novel site, Ser329. We provide evidence that Pim-2 is more efficient in directly phosphorylating c-Myc Ser329 to stabilize c-Myc. In contrast, we find that Pim-1 is more effective in mediating a decrease in c-Myc Thr58 phosphorylation and an increase in c-Myc Ser62 phosphorylation than in phosphorylating Ser329. In either case, through stabilizing c-Myc, Pim-1/Pim-2 kinases enhance the transcriptional activity of c-Myc. Also knocking down either Pim-1 or Pim-2 dramatically decreases the endogenous levels of c-Myc and thus, its transcriptional activity. Finally, coexpression of the Pim kinases and c-Myc enhances the transforming activity of c-Myc as does the phosphomimic mutant of c-Myc on Ser329. We conclude that these findings appear to explain at least in part the mechanism underlying the synergism between the Pim kinases and c-Myc in tumorigenesis.

• Authors: Y Zhang, Z Wang, X Li, N S Magnuson
• Journal: Oncogene (Oncogene) Vol. 27 Issue 35 Pg. 4809-19 (Aug 14 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 18438430 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Proto-Oncogene Proteins c-pim-1
• proto-oncogene proteins pim

Topics

• Animals
• Genes, myc
• Hydrolysis
• Mice
• Mice, Transgenic
• Phosphorylation
• Proto-Oncogene Proteins c-pim-1 (metabolism)