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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Neise, D. Sohn, D. Stefanski, A. Goto, H. Inagaki, M. Wesselborg, S. Budach, W. Stühler, K. Jänicke, R. U. |
| Description | Country affiliation: Germany Author Affiliation: Neise D ( Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.) |
| Abstract | The p90 ribosomal S6 kinase (RSK) family is a group of highly conserved Ser/Thr kinases that promote cell proliferation, growth, motility and survival. As they are almost exclusively activated downstream of extracellular signal-regulated kinases 1 and 2 (ERK1/2), therapeutic intervention by RSK inhibition is less likely to produce such severe side effects as those observed following inhibition of the upstream master regulators Raf, MEK and ERK1/2. Here, we report that BI-D1870, a potent small molecule inhibitor of RSKs, induces apoptosis, although preferentially, in a p21-deficient background. On the other hand, BI-D1870 also induces a strong transcription- and p53-independent accumulation of p21 protein and protects cells from gamma irradiation (γIR)-induced apoptosis, driving them into senescence even in the absence of γIR. Although we identified p21 in in vitro kinase assays as a novel RSK substrate that specifically becomes phosphorylated by RSK1-3 at Ser116 and Ser146, RNA-interference, overexpression and co-immunoprecipitation studies as well as the use of SL0101, another specific RSK inhibitor, revealed that BI-D1870 mediates p21 accumulation via a yet unknown pathway that, besides its off-site targets polo-like kinase-1 and AuroraB, also does also not involve RSKs. Thus, this novel off-target effect of BI-D1870 should be taken into serious consideration in future studies investigating the role of RSKs in cellular signaling and tumorigenesis. |
| File Format | HTM / HTML |
| e-ISSN | 20414889 |
| DOI | 10.1038/cddis.2013.386 |
| Journal | Cell Death and Disease |
| Volume Number | 4 |
| Language | English |
| Publisher | Nature Publishing Group |
| Publisher Date | 2013-10-17 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Gamma Rays Research Support, Non-u.s. Gov't Phosphorylation Stress, Physiological Substrate Specificity Cell Aging Pteridines Antagonists & Inhibitors Gene Knockdown Techniques Monosaccharides Tumor Suppressor Protein P53 Transcription, Genetic Ribosomal Protein S6 Kinases, 90-kda Hct116 Cells Isoenzymes Proto-oncogene Proteins Protein-serine-threonine Kinases Pharmacology Benzopyrans Aurora Kinases Metabolism Drug Effects Discipline Cell Biology Protein Kinase Inhibitors Radiation Effects Cyclin-dependent Kinase Inhibitor P21 Cell Cycle Proteins Phosphoserine Apoptosis |
| Content Type | Text |
| Resource Type | Article |
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