Requirement for Mdm2 in the survival effects of Bcr-Abl and interleukin 3 in hematopoietic cells.
The p53/Mdm2 pathway plays an important role in the induction of cell cycle arrest or apoptosis in response to genotoxic stress. Both the oncogene Bcr-Abl and physiological growth factors such as interleukin (IL)-3 can modulate the outcome of cellular exposure to DNA damage. To determine whether Bcr-Abl and growth factors can affect the p53/Mdm2 pathway, we studied the expression of Mdm2 in the IL-3-dependent pre-B cell line BaF3 and its bcr-abl-transfected derivative BaF3p185 after IL-3 deprivation or treatment with the c-Abl tyrosine kinase inhibitor STI571. We found that both growth factor withdrawal and inhibition of Bcr-Abl kinase lead to a down-regulation of Mdm2 preceding the induction of apoptosis. Apoptotic cell death induced by STI571 is partially dependent on p53. The early decrease of Mdm2 protein was not attributable to transcriptional regulation or to caspase-mediated cleavage. On the other hand, it could be completely blocked by the proteasomal inhibitor lactacystin. Targeted down-regulation of Mdm2 protein by antisense oligodeoxynucleotides overcame the survival effects of IL-3 and Bcr-Abl and resulted in accelerated apoptosis. Taken together, survival signals provided either by physiological growth factors or by oncogenic Bcr-Abl can positively regulate Mdm2, whereas Mdm2 ablation can reduce cell survival. These findings imply that, similarly to physiological growth factors such as IL-3, Bcr-Abl can promote cell survival through modulating the p53-Mdm2 pathway.
Goetz
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Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany.
van der Kuip
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H
Maya
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Oren
M
M
Aulitzky
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WE
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D001549:Benzamides; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000494:pharmacology / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D051736:Proto-Oncogene Proteins c-mdm2; D011743:Pyrimidines / Q000494:pharmacology; D014162:Transfection
D001549:Benzamides; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex