STAT5-Dependent CyclinD1 and Bcl-xL Expression in Bcr-Abl-Transformed Cells

Groot, Rolf P. de; Raaijmakers, J. A. M.; Lammers, Jan‐Willem J.; Koenderman, Leo

doi:10.1006/mcbr.2000.0231

Cited by 127 publications

(115 citation statements)

References 58 publications

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“…Further, Western analysis showed that the synBcr-Abl siRNA down-regulated the anti-apoptotic Bcl-X L protein significantly compared to an irrelevant control siRNA ( Figure 3A). This supports the observed relationship between Bcr-Abl and Bcl-X L expression [17,18].…”

Section: Resultssupporting

confidence: 90%

Effects of siRNAs in combination with Gleevec on K-562 cell proliferation and Bcr-Abl expression

2006

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SummaryRNA interference (RNAi) is the repression of gene expression through a cellular mechanism of transcriptspecific mRNA degradation. RNAi has been observed in human cells and applied to the modulation of a variety of human transcripts. Our goals were to deliver small interfering RNA (siRNA) using a liposomebased method, and to show Bcr-Abl siRNA specificity against K-562 cells, alone or in combination with Gleevec. Both synthetic (syn) siRNA, consisting of homogeneous 21-nucleotide-long RNA duplexes specific for the Bcr-Abl fusion site, and recombinant (r)-generated Bcr-Abl siRNA were employed. siRNA was transfected into K-562 cells with greater than 90% efficiency using RNAiFectä, as judged by fluorescence analysis. The Bcr-Abl transcript was inhibited using either siRNA preparation as measured by RT-PCR or real-time PCR. The IC 50 of Gleevec in the K-562 subline F 1 was lowered over 3-fold from 0.2 to 0.06 lM in cells transfected with either syn or rBcr-Abl siRNA. No effect was observed in cells after transfection with an irrelevant control siRNA. Therefore, K-562 cells transfected with RNAifect deliver Bcr-Abl siRNA efficiently and the Bcr-Abl siRNA decreased the IC 50 of Gleevec required to inhibit the high levels of BcrAbl protein found in K-562 cells.

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Section: Resultssupporting

confidence: 90%

Effects of siRNAs in combination with Gleevec on K-562 cell proliferation and Bcr-Abl expression

2006

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“…In F-36P cells, IL-3 induced cyclin D1 expression was shown to be inhibited by dominant negative-STAT5, while constitutively activated-STAT5 induced IL-3 independent cyclin D1 promoter activity (Simonart et al, 2000). Indeed, the cyclin D1 promoter was shown to contain binding sites for STAT3 and -5 (Bromberg et al, 1999;Matsumura et al, 1999;de Groot et al, 2000). Our results show that like IL-3, hypoxia induces STAT5 binding to the GAS1 in the cyclin D1 promoter as well as increased cyclin D1 promoter activity ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

Joung

Lim²,

Lee³

et al. 2005

Exp Mol Med

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Hypoxia, a common consequence of solid tumor growth in breast cancer or other cancers, serves to propagate a cascade of molecular pathways which include angiogenesis, glycolysis, and various cellcycle control proteins. As we have shown previously, hypoxia activates STAT5 (signal transducer and activator of transcription 5) and increases its binding activity to the GAS element in mammary epithelial cells. In this study we attempted to elucidate the mechanism by which cyclin D1 is regulated by the STAT5 protein under hypoxic conditions. Our data demonstrate that hypoxia (2% O 2 ) or desferrioxamine (DFO) induces tyrosine and serine phosphorylation of STAT5 in human breast cancer cells (MCF-7) and mammary epithelial cells (HC11). Imunoprecipitation and subsequent Western analysis showed that Jak2 leads to the tyrosine phosphorylation and activation of STAT5a or STAT5b under hypoxic conditions. Using a transfected COS-7 cell model system, we demonstrate that the activity of a cyclin D1 promoter-luciferase construct increased under hypoxic conditions or DFO treatment. The activity of the STAT5b/cyclin D1 promoter increased significantly by 12 h of hypoxia, whereas the activity of the STAT5a/cyclin D1 promoter was unaffected under hypoxic conditions. These increases in promoter activity are predominantly mediated by the Jak2/ STAT5b signaling pathway. We have shown by EMSA that hypoxia induces STAT5 to bind to the cyclin D1 promoter (GAS-1) in MCF-7 and HC11 cells. These data suggest that STAT5b may mediate the transcriptional activation of cyclin D1 after hypoxic stimulation.

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“…2 Resistance mechanisms to nilotinib were also described and attributed to either mutations in the tyrosine kinase domain of BCR-ABL 3 or BCR-ABL over-expression. 4 BCR-ABL expression confers an apoptotic-resistant phenotype to the cells, which has been attributed to the expression of antiapoptotic proteins such as BCL-XL [5][6][7] and MCL-1, 8,9 and the downregulation of the proapoptotic protein BIM. 9,10 Both imatinib and the second-generation inhibitor nilotinib induce apoptosis of BCR-ABL-expressing cells, and this apoptosis is completely dependent on the expression of BIM.…”

Section: Introductionmentioning

confidence: 99%

The stem cell factor–c-KIT pathway must be inhibited to enable apoptosis induced by BCR–ABL inhibitors in chronic myelogenous leukemia cells

et al. 2009

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Imatinib is an effective first-line therapy for chronic myelogenous leukemia (CML) that acts by targeting the tyrosine kinase activity of BCR-ABL. To overcome resistance, secondgeneration inhibitors of BCR-ABL have been developed. Among these, nilotinib is more potent against BCR-ABL than imatinib, and is effective against many imatinib-resistant BCR-ABL mutants. In this study, an in vitro flow cytometry assay to analyze imatinib-and nilotinib-induced apoptosis in CML cells has been developed. Both the drugs induced significant apoptosis in CD34 þ cells from 36 CML bone marrow samples (Po10 À4 ), whereas CD34 þ cells from BCR-ABL negative samples were unaffected. When the experiments were carried out in the presence of a cocktail of cytokines, nilotinib-but not imatinib-induced apoptosis was inhibited. This differential inhibition was confirmed on K562 cells. A blocking anti-CD117 antibody alleviated the antiapoptotic effect of cytokines against nilotinib. Moreover, using short hairpin RNA against BCR-ABL, we showed that K562 cells were not dependent on BCR-ABL signaling as long as the stem cell factor (SCF) receptor pathway was activated. We conclude that the c-KIT pathway may substitute for BCR-ABL tyrosine kinase to activate survival signals, and that c-KIT must be inhibited besides Bcr-Abl to allow apoptosis of CML cells.

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STAT5-Dependent CyclinD1 and Bcl-xL Expression in Bcr-Abl-Transformed Cells

Cited by 127 publications

References 58 publications

Effects of siRNAs in combination with Gleevec on K-562 cell proliferation and Bcr-Abl expression

Effects of siRNAs in combination with Gleevec on K-562 cell proliferation and Bcr-Abl expression

Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

The stem cell factor–c-KIT pathway must be inhibited to enable apoptosis induced by BCR–ABL inhibitors in chronic myelogenous leukemia cells

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