title: 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.affiliation: School of Molecular Biosciences, Washington State University, Pullman, WA 99163, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: N S
authors.initials: NS
authors.lastname: Magnuson
mesh_terms: D000818:Animals; D016259:Genes, myc; D006868:Hydrolysis; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*
chemical_list: D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim