title: Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells.
abstract: Abl-mediated transformation requires the activation of multiple pathways involved in the cellular proliferation and survival, including PI3K/AKT and JAK/STAT-dependent Pim kinases. Recently, the E17K mutation in the AKT1 has been associated with multiple human malignancies and leukemia in mice. However, this mutation has not been identified in Abl-transformed cells. We investigated the presence of the AKT1(E17K) mutation in v-Abl-transformed cell clones. AKT1(E17K) was detected in 3 (2.6%) of 116 specimens examined. To show the involvement of AKT1(E17K) directly in v-Abl-mediated tumorigenesis, we infected bone marrow cells from mice with bicistronic retroviruses encoding v-Abl and either wild-type or the mutant AKT1. Interestingly, we found that E17K mutant greatly increased the v-Abl transformation efficiency as compared with wild-type AKT1. Ectopic expression of E17K mutant increased the expression levels of antiapoptotic protein BCL2 and phosphorylation levels of proapoptotic protein BAD. This correlated with an increased protection from imatinib-induced apoptosis in Abl transformants. Furthermore, AKT1(E17K) promotes survival of the Pim-deficient cells, indicating a functional link between AKT and Pim in v-Abl transformation. In addition, AKT1(E17K) delays loss of Pim-1 and Pim-2 protein levels on v-Abl inactivation, which suggests that there exists reciprocal signaling between AKT and Pim in v-Abl transformants.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: G
authors.initials: G
authors.lastname: Guo
authors.forename: X
authors.initials: X
authors.lastname: Qiu
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: P B
authors.initials: PB
authors.lastname: Rothman
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.forename: J-L
authors.initials: JL
authors.lastname: Chen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001798:Blood Proteins / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D006801:Humans; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000502:physiology*
chemical_list: D001798:Blood Proteins; D010750:Phosphoproteins; C039077:platelet protein P47; C494918:AKT1 protein, human; C496636:Pim1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1