Abstract
The Bcr-abl oncogene induces hematopoietic cell transformation and protects cells from apoptosis; however, the mechanisms whereby Bcr-abl blocks apoptosis are poorly defined. We examined whether the inhibitor of apoptosis protein (IAP) family, in particular survivin, are regulated by Bcr-abl. Overexpression of Bcr-abl in Mo7e or BaF3 hematopoietic cells elevated survivin mRNA and protein concomitant with a 4-fold increase in survivin promoter activity. The region of the survivin promoter responding to Bcr-abl was narrowed down to a 116 bp fragment between nucleotides -1,194 and -1,078. The IAP family member IAP-like protein-2 was also up-regulated by Bcr-abl. Disruption of Bcr-abl in Bcr-abl-transduced BaF3 cells by small interfering RNA resulted in 3- to 4-fold reduction in survivin protein confirming the link between Bcr-abl and survivin. Survivin disruption in Bcr-abl-transduced Mo7e cells, or in K562 cells that endogenously express Bcr-abl, by transfection with dominant-negative or antisense survivin constructs promoted apoptosis induced by the Bcr-abl tyrosine kinase inhibitor STI571, which was accompanied by caspase-dependent cleavage of Bcr-abl, mitochondrial membrane potential disruption, and enhanced mitochondrial cytochrome c release. Although ectopic survivin protected K562 cells from apoptosis induced by STI571, it did not protect cells from apoptosis induced either by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of TRAIL plus Hemin. Our results identify a new signal pathway downstream of Bcr-abl, in addition to the Bcl-2 family involved in the antiapoptotic effects of Bcr-abl, and suggest that anti-survivin therapy may have utility in patients with chronic myelogenous leukemia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / genetics
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Apoptosis Regulatory Proteins / pharmacology
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Benzamides
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Caspase 9
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Caspases / metabolism
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Cell Line, Tumor
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Cytochromes c / metabolism
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Fusion Proteins, bcr-abl / biosynthesis
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / physiology*
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / physiology
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Humans
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Imatinib Mesylate
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Inhibitor of Apoptosis Proteins
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K562 Cells
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Leukemia, Megakaryoblastic, Acute / drug therapy
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Leukemia, Megakaryoblastic, Acute / genetics
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Leukemia, Megakaryoblastic, Acute / metabolism
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Leukemia, Megakaryoblastic, Acute / pathology
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Membrane Glycoproteins / pharmacology
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Mice
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Microtubule-Associated Proteins / antagonists & inhibitors*
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Oligonucleotides, Antisense / genetics
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Piperazines / pharmacology*
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Pyrimidines / pharmacology*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Signal Transduction
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Survivin
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TNF-Related Apoptosis-Inducing Ligand
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Transduction, Genetic
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BIRC5 protein, human
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Benzamides
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Inhibitor of Apoptosis Proteins
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Membrane Glycoproteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Oligonucleotides, Antisense
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Piperazines
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Pyrimidines
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RNA, Messenger
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Survivin
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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Imatinib Mesylate
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Cytochromes c
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Fusion Proteins, bcr-abl
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CASP9 protein, human
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Casp9 protein, mouse
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Caspase 9
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Caspases