Pim kinase-dependent inhibition of c-Myc degradation

• Published in: Oncogene Vol. 27; no. 35; pp. 4809 - 4819
• Main Authors: ZHANG, Y, WANG, Z, LI, X, MAGNUSON, N. S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 14.08.2008; Nature Publishing Group
• Subjects: Animals; B-cell lymphoma; Beta cells; Biochemistry; Biological and medical sciences; c-Myc protein; Cancer; Carcinogenesis; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Fundamental and applied biological sciences. Psychology; Gene expression; Genes, myc; Genetic aspects; Health aspects; Hydrolysis; Kinases; Lymphoma; Mice; Mice, Transgenic; Molecular and cellular biology; Myc protein; Oncogenes; Pancreatic cancer; Phosphorylation; Prostate cancer; Protein kinases; Proto-Oncogene Proteins c-pim-1 - metabolism; Risk factors; Rodents; Transcription; Tumorigenesis; United States; Phosphorylation; stabilization; Enzyme; Kinase; c-Myc; Transferases; C-Onc gene; Inhibition; Carcinogenesis; Protooncogene; Pim-1/Pim-2
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.123

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.