title: eIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes.
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 RNA interference-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 Abl-transformed 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.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.
authors.forename: Jianling
authors.initials: J
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Guijie
authors.initials: G
authors.lastname: Guo
authors.forename: Ruijiao
authors.initials: R
authors.lastname: Xi
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
authors.forename: Douglas
authors.initials: D
authors.lastname: Whitten
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D016313:Genes, abl / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D039642:Eukaryotic Initiation Factors; C031799:eIF-4B; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim