title: Functional cooperation among Ras, STAT5, and phosphatidylinositol 3-kinase is required for full oncogenic activities of BCR/ABL in K562 cells.
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.
authors.affiliation: Department of Hematology/Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Sonoyama
authors.forename: Itaru
authors.initials: I
authors.lastname: Matsumura
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ezoe
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Satoh
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kataoka
authors.forename: Emi
authors.initials: E
authors.lastname: Takai
authors.forename: Masao
authors.initials: M
authors.lastname: Mizuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Machii
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakao
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
mesh_terms: D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D019925:Cyclin A / Q000096:biosynthesis; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D005799:Genes, Dominant; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D016898:Interferon-alpha / Q000494:pharmacology; D020014:K562 Cells; D008156:Luciferases / Q000378:metabolism; D008894:Milk Proteins; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D017304:Annexin A5; C494811:BCL2L1 protein, human; C080336:CCND2 protein, human; C534696:CCND3 protein, human; D004396:Coloring Agents; D019925:Cyclin A; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D016898:Interferon-alpha; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D003907:Dexamethasone; D004247:DNA; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D018631:ras Proteins