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Requirement for SAPK–JNK signaling in the induction of apoptosis by ribosomal stress in REH lymphoid leukemia cells

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Abstract

The present studies examined performance of SAPK cascades and apoptotic commitment following ribosomal trauma in REH lymphoid leukemia cells. Ribostatic insults included disruption of ribosomal activity by mechanistically dissimilar agents such as blasticidin-S (BCS) (which binds 28S-rRNA to block peptidyl bond formation), kasugamycin (KSM) (which binds 18S-rRNA to prevent translational initiation), and cycloheximide (CHX) (which blocks A-site to P-site translocation of peptidyl-tRNA). Exposure of REH cells to BCS elicited DNA degradation and apoptotic cytolysis. BCS stimulated JNK1/JNK2 and p38, and their shared targets c-Jun and ATF2. Inhibition of JNK1/JNK2 (but not of p38) antagonized blasticidin-induced apoptosis, whereas targeting alternative ribosomal sites with KSM or CHX limited translation, but failed to activate the SAPK cascade or initiate apoptosis. Our findings indicate that interference with 28S-rRNA by BCS initiates apoptosis in REH cells through recruitment of SAPK–JNK signaling. Disparities between the lethal actions of BCS, KSM, and CHX appear to reflect established differences in the subribosomal targets of these agents. We propose that the SAPK cascade comprises an essential mechanism for the transduction of specific lethal stress signals emanating from active ribosomes, and that interference with the 28S-rRNA, rather than the peptidyl transfer center of the large subunit, is critical to apoptotic commitment.

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Acknowledgements

This work was supported primarily through NIH-NCI research Grants 5K01 CA-082404 (WDJ) and 5R01 CA-100283 (PPR). We thank Dr Ferid Murad for provision of generous transitional support through UTHSC-H core resource funds. This work is dedicated to the memory of Dr Esteban E Sierra.

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Authors and Affiliations

  1. Department of Integrative Biology & Pharmacology, University of Texas Health Sciences Center – Houston, Houston, TX, USA

    C R Johnson, T Jiffar, P P Ruvolo & W D Jarvis

  2. Department of Cardiovascular Surgery, University of Cologne, Cologne, Germany

    U M Fischer

  3. The Institute for Molecular Medicine, University of Texas Health Sciences Center – Houston, Houston, TX, USA

    P P Ruvolo & W D Jarvis

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  1. C R Johnson
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  2. T Jiffar
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  4. P P Ruvolo
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Johnson, C., Jiffar, T., Fischer, U. et al. Requirement for SAPK–JNK signaling in the induction of apoptosis by ribosomal stress in REH lymphoid leukemia cells. Leukemia 17, 2140–2148 (2003). https://doi.org/10.1038/sj.leu.2403132

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  • DOI: https://doi.org/10.1038/sj.leu.2403132

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