RRC ID 41479
Author Sonoyama J, Matsumura I, Ezoe S, Satoh Y, Zhang X, Kataoka Y, Takai E, Mizuki M, Machii T, Wakao H, Kanakura Y.
Title Functional cooperation among Ras, STAT5, and phosphatidylinositol 3-kinase is required for full oncogenic activities of BCR/ABL in K562 cells.
Journal J. Biol. Chem.
Abstract BCR/ABL tyrosine kinase generated from the chromosomal translocation t(9;22) causes chronic myelogenous leukemia and acute lymphoblastic leukemia. To examine the roles of BCR/ABL-activated individual signaling molecules and their cooperation in leukemogenesis, we inducibly expressed a dominant negative (DN) form of Ras, phosphatidylinositol 3-kinase, and STAT5 alone or in combination in p210 BCR/ABL-positive K562 cells. The inducibly expressed DN Ras (N17), STAT5 (694F), and DN phosphatidylinositol 3-kinase (Delta p85) inhibited the growth by 90, 55, and 40%, respectively. During the growth inhibition, the expression of cyclin D2 and cyclin D3 was suppressed by N17, 694F, or Delta p85; that of cyclin E by N17; and that of cyclin A by Delta p85. In addition, N17 induced apoptosis in a small proportion of K562, whereas 694F and Delta p85 were hardly effective. In contrast, coexpression of two DN mutants in any combinations induced severe apoptosis. During these cultures, the expression of Bcl-2 was suppressed by N17, 694F, or Delta p85, and that of Bcl-XL by N17. Furthermore, although K562 was resistant to interferon-alpha- and dexamethasone-induced apoptosis, disruption of one pathway by N17, 694F, or Delta p85 sensitized K562 to these reagents. These results suggested that cooperation among these molecules is required for full leukemogenic activities of BCR/ABL.
Volume 277(10)
Pages 8076-82
Published 2002-3-8
DOI 10.1074/jbc.M111501200
PII M111501200
PMID 11779872
MeSH Annexin A5 / pharmacology Apoptosis Blotting, Northern Blotting, Western Caspase 3 Caspases / metabolism Cell Cycle Cell Division Coloring Agents / pharmacology Cyclin A / biosynthesis Cyclin D2 Cyclin D3 Cyclins / biosynthesis DNA / metabolism DNA, Complementary / metabolism DNA-Binding Proteins / metabolism* Dexamethasone / pharmacology Fusion Proteins, bcr-abl / metabolism* Genes, Dominant Glucocorticoids / pharmacology Humans In Situ Nick-End Labeling Interferon-alpha / pharmacology K562 Cells Luciferases / metabolism Milk Proteins* Mutation Phosphatidylinositol 3-Kinases / metabolism* Plasmids / metabolism Protein Binding Proto-Oncogene Proteins c-bcl-2 / metabolism STAT5 Transcription Factor Signal Transduction Time Factors Trans-Activators / metabolism* Tumor Suppressor Proteins bcl-X Protein ras Proteins / metabolism*
IF 4.011
Times Cited 78
Human and Animal Cells