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Differential Requirement for the Stress-Activated Protein Kinase/c-Jun NH2-Terminal Kinase in RNA Damage-Induced Apoptosis in Primary and in Immortalized Fibroblasts
- Source :
- Molecular Cell Biology Research Communications. 4:122-128
- Publication Year :
- 2000
- Publisher :
- Elsevier BV, 2000.
-
Abstract
- Onconase, an anticancer ribonuclease, damages cellular tRNA and causes caspase-dependent apoptosis in targeted cells (M. S. Iordanov, O. P. Ryabinina, J. Wong, T. H. Dinh, D. L. Newton, S. M. Rybak, and B. E. Magun. Cancer Res. 60, 1983–1994, 2000). The proapoptotic action of onconase depends on its RNase activity, but the molecular mechanisms leading to RNA damage-induced caspase activation are completely unknown. In this study, we have investigated whether onconase activates two signal-transduction pathways commonly stimulated by conventional chemo- and radiotherapy, namely the stress-activated protein kinase (SAPK) cascade and the pathway leading to the activation of nuclear factor-kappa B (NF-κB). We found that, in all cell types tested, onconase is a potent activator of SAPK1 (JNK1 and JNK2) and SAPK2 (p38 MAP kinase), but that it is incapable of activating NF-κB. Inhibition of p38 MAP kinase activity with a pharmacological inhibitor, SB203580, demonstrated that p38 MAP kinase is not required for onconase cytotoxicity. Using explanted fibroblasts from mice that contain targeted disruption of both jnk1 and jnk2 alleles, we found that JNKs are important mediators of onconase-induced cytotoxicity. Surprisingly, following the immortalization of these same cells with human papilloma virus (HPV16) gene products E6 and E7, additional proapoptotic pathways (exclusive of JNK) were provoked by onconase. Our results demonstrate that onconase may activate proapoptotic pathways in tumor cells that are not able to be accessed in normal cells. These results present the possibility that the cytotoxic activity of onconase in normal cells may be reduced by blocking the activity of JNKs.
- Subjects :
- Cell Survival
Papillomavirus E7 Proteins
p38 mitogen-activated protein kinases
Immunoblotting
Apoptosis
Nerve Tissue Proteins
Biology
Mitogen-activated protein kinase kinase
Transfection
p38 Mitogen-Activated Protein Kinases
Ligases
Synaptotagmins
Tumor Cells, Cultured
Humans
Cytotoxic T cell
Mitogen-Activated Protein Kinase 8
Enzyme Inhibitors
Phosphorylation
Hematoxylin
Protein kinase A
Molecular Biology
Membrane Glycoproteins
MAP kinase kinase kinase
Tumor Necrosis Factor-alpha
Activator (genetics)
Calcium-Binding Proteins
NF-kappa B
Oncogene Proteins, Viral
Cell biology
Enzyme Activation
Caspases
Mitogen-activated protein kinase
biology.protein
Eosine Yellowish-(YS)
RNA
Mitogen-Activated Protein Kinases
HeLa Cells
Subjects
Details
- ISSN :
- 15224724
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- Molecular Cell Biology Research Communications
- Accession number :
- edsair.doi.dedup.....fc3ad33c5a52e9d3c4714736ad8a8b5a