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Activation of Bak and Bax through c-abl-protein kinase Cdelta-p38 MAPK signaling in response to ionizing radiation in human non-small cell lung cancer cells.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2006 Mar 17; Vol. 281 (11), pp. 7049-59. Date of Electronic Publication: 2006 Jan 12. - Publication Year :
- 2006
-
Abstract
- Intracellular signaling molecules and apoptotic factors seem to play an important role in determining the radiation response of tumor cells. However, the basis for the link between signaling pathway and apoptotic cell death machinery after ionizing irradiation remains still largely unclear. In this study, we showed that c-Abl-PKCdelta-Rac1-p38 MAPK signaling is required for the conformational changes of Bak and Bax during ionizing radiation-induced apoptotic cell death in human non-small cell lung cancer cells. Ionizing radiation induced conformational changes and subsequent oligomerizations of Bak and Bax, dissipation of mitochondrial membrane potential, and cytochrome c release from mitochondria. Small interference (siRNA) targeting of Bak and Bax effectively protected cells from radiation-induced mitochondrial membrane potential loss and apoptotic cell death. p38 MAPK was found to be selectively activated in response to radiation treatment. Inhibition of p38 MAPK completely suppressed radiation-induced Bak and Bax activations, dissipation of mitochondrial membrane potential, and cell death. Moreover, expression of a dominant negative form of protein kinase Cdelta (PKCdelta) or siRNA targeting of PKCdelta attenuated p38 MAPK activation and conformational changes of Bak and Bax. In addition, ectopic expression of RacN17, a dominant negative form of Rac1, markedly inhibited p38 MAPK activation but did not affect PKCdelta activation. Upon stimulation of cells with radiation, PKCdelta was phosphorylated dramatically on tyrosine. c-Abl-PKCdelta complex formation was also increased in response to radiation. Moreover, siRNA targeting of c-Abl attenuated radiation-induced PKCdelta and p38 MAPK activations, and Bak and Bax modulations. These data support a notion that activation of the c-Abl-PKCdelta-Rac1-p38 MAPK pathway in response to ionizing radiation signals conformational changes of Bak and Bax, resulting in mitochondrial activation-mediated apoptotic cell death in human non-small cell lung cancer cells.
- Subjects :
- Apoptosis
Blotting, Western
Cell Death
Cell Line
Cell Line, Tumor
Cell Separation
Cross-Linking Reagents pharmacology
Cytosol metabolism
Enzyme Activation
Flow Cytometry
Humans
Immunoprecipitation
MAP Kinase Signaling System
Membrane Potentials
Mitochondria metabolism
Phosphorylation
Protein Conformation
RNA, Small Interfering metabolism
Radiation, Ionizing
Signal Transduction
Time Factors
Transfection
Tyrosine chemistry
Carcinoma, Non-Small-Cell Lung metabolism
Lung Neoplasms metabolism
Protein Kinase C metabolism
Proto-Oncogene Proteins c-abl metabolism
bcl-2 Homologous Antagonist-Killer Protein metabolism
bcl-2-Associated X Protein metabolism
p38 Mitogen-Activated Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 281
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16410245
- Full Text :
- https://doi.org/10.1074/jbc.M512000200