Differential requirement for the stress-activated protein kinase/c-Jun NH2-terminal kinase in RNA damage-induced apoptosis in primary and in immortalized fibroblasts

Mihail S. Iordanov, John Wong, Dianne L. Newton, Susanna M. Rybak, Robert K. Bright, Richard A. Flavell, Roger J. Davis, Bruce E. Magun

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)122-128
Number of pages7
JournalMolecular Cell Biology Research Communications
Volume4
Issue number2
DOIs
StatePublished - 2000

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JNK Mitogen-Activated Protein Kinases
Heat-Shock Proteins
Protein Kinases
Fibroblasts
RNA
Apoptosis
p38 Mitogen-Activated Protein Kinases
Ribonucleases
Caspases
Papillomaviridae
Mitogen-Activated Protein Kinase 11
ranpirnase
MAP Kinase Signaling System
NF-kappa B
Transfer RNA
Signal Transduction
Neoplasms
Radiotherapy
Alleles
Pharmacology

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Differential requirement for the stress-activated protein kinase/c-Jun NH2-terminal kinase in RNA damage-induced apoptosis in primary and in immortalized fibroblasts. / Iordanov, Mihail S.; Wong, John; Newton, Dianne L.; Rybak, Susanna M.; Bright, Robert K.; Flavell, Richard A.; Davis, Roger J.; Magun, Bruce E.

In: Molecular Cell Biology Research Communications, Vol. 4, No. 2, 2000, p. 122-128.

Research output: Contribution to journalArticle

Iordanov, Mihail S. ; Wong, John ; Newton, Dianne L. ; Rybak, Susanna M. ; Bright, Robert K. ; Flavell, Richard A. ; Davis, Roger J. ; Magun, Bruce E. / Differential requirement for the stress-activated protein kinase/c-Jun NH2-terminal kinase in RNA damage-induced apoptosis in primary and in immortalized fibroblasts. In: Molecular Cell Biology Research Communications. 2000 ; Vol. 4, No. 2. pp. 122-128.
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AU - Bright, Robert K.

AU - Flavell, Richard A.

AU - Davis, Roger J.

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AB - 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.

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