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Activation of c-Abl tyrosine kinase requires caspase activation and is not involved in JNK/SAPK activation during apoptosis of human monocytic leukemia U937 cells.
- Source :
-
Oncogene [Oncogene] 1999 Feb 11; Vol. 18 (6), pp. 1277-83. - Publication Year :
- 1999
-
Abstract
- Genotoxic stress triggers the activation of several sensor molecules, such as p53, JNK1/SAPK and c-Abl, and occasionally promotes the cells to apoptosis. We previously reported that JNK1/SAPK regulates genotoxic stress-induced apoptosis in p53-negative U937 cells by activating caspases. c-Abl is expected to act upstream of JNK1/SAPK activation upon treatment with genotoxic stressors, but its involvement in apoptosis development is still unclear. We herein investigated the kinase activities of c-Abl and JNK1/SAPK during apoptosis elicited by genotoxic anticancer drugs and tumor necrosis factor (TNF) in U937 cells and their apoptosis-resistant variant UK711 cells. We found that the activation of JNK1/SAPK and c-Abl correlated well with apoptosis development in these cell lines. Unexpectedly, however, the JNK1/SAPK activation preceded the c-Abl activation. Moreover, the caspase inhibitor Z-Asp suppressed c-Abl activation and the onset of apoptosis but not the JNK1/SAPK activation. Interestingly, c-Abl tyrosine kinase inhibition by CGP 57148 reduced apoptosis without interfering with JNK1/SAPK activation. These results indicate that c-Abl acts not upstream of JNK1/ SAPK but downstream of caspases during the development of p53-independent apoptosis and is possibly involved in accelerating execution of the cell death pathway.
- Subjects :
- Aspartic Acid analogs & derivatives
Aspartic Acid pharmacology
Benzamides
Caspase Inhibitors
Enzyme Activation
Humans
Imatinib Mesylate
JNK Mitogen-Activated Protein Kinases
Piperazines pharmacology
Proto-Oncogene Proteins c-abl antagonists & inhibitors
Pyrimidines pharmacology
U937 Cells
Apoptosis
Calcium-Calmodulin-Dependent Protein Kinases metabolism
Caspases metabolism
Leukemia, Myeloid physiopathology
Mitogen-Activated Protein Kinases
Proto-Oncogene Proteins c-abl metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 18
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 10022809
- Full Text :
- https://doi.org/10.1038/sj.onc.1202423