EIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes

Jianling Yang, Jun Wang, Ke Chen, Guijie Guo, Ruijiao Xi, Paul B Rothman, Douglas Whitten, Lianfeng Zhang, Shile Huang, Ji Long Chen

Research output: Contribution to journalArticle

Abstract

Alterations in translation occur in cancer cells, but the precise pathogenic processes and mechanistic underpinnings are not well understood. In this study, we report that interactions between Pim family kinases and the translation initiation factor eIF4B are critical for Abl oncogenicity. Pim kinases, Pim-1 and Pim-2, both directly phosphorylated eIF4B on Ser406 and Ser422. Phosphorylation of eIF4B on Ser422 was highly sensitive to pharmacologic or RNAinterference-mediated inhibition of Pim kinases. Expression and phosphorylation of eIF4B relied upon Abl kinase activity in both v-Abl- and Bcr-Abl-expressing leukemic cells based on their blockade by the Abl kinase inhibitor imatinib. Ectopic expression of phosphomimetic mutants of eIF4B conferred resistance to apoptosis by the Pim kinase inhibitor SMI-4a in Abl-transformed cells. In contrast, silencing eIF4B sensitized Abltransformed cells to imatinib-induced apoptosis and also inhibited their growth as engrafted tumors in nude mice. Extending these observations, we found that primary bone marrow cells derived from eIF4B-knockdown transgenic mice were less susceptible to Abl transformation, relative to cells from wild-type mice. Taken together, our results identify eIF4B as a critical substrate of Pim kinases in mediating the activity of Abl oncogenes, and they highlight eIF4B as a candidate therapeutic target for treatment of Abl-induced cancers.

Original languageEnglish (US)
Pages (from-to)4898-4908
Number of pages11
JournalCancer Research
Volume73
Issue number15
DOIs
StatePublished - Aug 1 2013

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abl Genes
Phosphorylation
Proto-Oncogene Proteins c-pim-1
Phosphotransferases
Apoptosis
proto-oncogene proteins pim
eIF-4B
Neoplasms
Peptide Initiation Factors
Nude Mice
Bone Marrow Cells
Transgenic Mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

EIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes. / Yang, Jianling; Wang, Jun; Chen, Ke; Guo, Guijie; Xi, Ruijiao; Rothman, Paul B; Whitten, Douglas; Zhang, Lianfeng; Huang, Shile; Chen, Ji Long.

In: Cancer Research, Vol. 73, No. 15, 01.08.2013, p. 4898-4908.

Research output: Contribution to journalArticle

Yang, J, Wang, J, Chen, K, Guo, G, Xi, R, Rothman, PB, Whitten, D, Zhang, L, Huang, S & Chen, JL 2013, 'EIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes', Cancer Research, vol. 73, no. 15, pp. 4898-4908. https://doi.org/10.1158/0008-5472.CAN-12-4277
Yang, Jianling ; Wang, Jun ; Chen, Ke ; Guo, Guijie ; Xi, Ruijiao ; Rothman, Paul B ; Whitten, Douglas ; Zhang, Lianfeng ; Huang, Shile ; Chen, Ji Long. / EIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes. In: Cancer Research. 2013 ; Vol. 73, No. 15. pp. 4898-4908.
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