title: AKT1 induces caspase-mediated cleavage of the CDK inhibitor p27Kip1 during cell cycle progression in leukemia cells transformed by FLT3-ITD.
abstract: p27Kip1 cleavage and caspase-3 regulate cell cycle in human myeloma cells and B cells, however regulation of p27Kip1 cleavage during the cell cycle is not known. In BaF3-FLT3-ITD cells, p27Kip1 undergoes C-terminal cleavage. Inhibition of the PI3K/AKT pathway is associated with decreased cleavage of p27Kip1 and G1 phase arrest. A caspase-3 inhibitor reduces p27Kip1 cleavage and inhibits cell proliferation. Knockdown shRNA against AKT1 reduces cleavage of p27Kip1, inhibits caspase-3 activation, and is associated with a delay in cell cycle progression. Taken together, these findings indicate that AKT1 induces caspase-mediated cleavage of p27Kip1, required for G1-S progression in FLT3-ITD cells.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02115, USA.
authors.forename: Xinping
authors.initials: X
authors.lastname: Yang
authors.forename: Suiyang
authors.initials: S
authors.lastname: Liu
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020080:Tandem Repeat Sequences; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: C436291:CDKN1B protein, human; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases