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The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1.
Cell Death Dis. 2013 Oct 17; 4:e859.CD

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.

Authors+Show Affiliations

Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Universitätsstrasse 1, Düsseldorf 40225, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24136223

Citation

Neise, D, et al. "The P90 Ribosomal S6 Kinase (RSK) Inhibitor BI-D1870 Prevents Gamma Irradiation-induced Apoptosis and Mediates Senescence Via RSK- and P53-independent Accumulation of P21WAF1/CIP1." Cell Death & Disease, vol. 4, 2013, pp. e859.
Neise D, Sohn D, Stefanski A, et al. The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1. Cell Death Dis. 2013;4:e859.
Neise, D., Sohn, D., Stefanski, A., Goto, H., Inagaki, M., Wesselborg, S., Budach, W., Stühler, K., & Jänicke, R. U. (2013). The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1. Cell Death & Disease, 4, e859. https://doi.org/10.1038/cddis.2013.386
Neise D, et al. The P90 Ribosomal S6 Kinase (RSK) Inhibitor BI-D1870 Prevents Gamma Irradiation-induced Apoptosis and Mediates Senescence Via RSK- and P53-independent Accumulation of P21WAF1/CIP1. Cell Death Dis. 2013 Oct 17;4:e859. PubMed PMID: 24136223.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1. AU - Neise,D, AU - Sohn,D, AU - Stefanski,A, AU - Goto,H, AU - Inagaki,M, AU - Wesselborg,S, AU - Budach,W, AU - Stühler,K, AU - Jänicke,R U, Y1 - 2013/10/17/ PY - 2013/07/15/received PY - 2013/08/16/revised PY - 2013/09/05/accepted PY - 2013/10/19/entrez PY - 2013/10/19/pubmed PY - 2014/3/13/medline SP - e859 EP - e859 JF - Cell death & disease JO - Cell Death Dis VL - 4 N2 - 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. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/24136223/The_p90_ribosomal_S6_kinase__RSK__inhibitor_BI_D1870_prevents_gamma_irradiation_induced_apoptosis_and_mediates_senescence_via_RSK__and_p53_independent_accumulation_of_p21WAF1/CIP1_ L2 - http://dx.doi.org/10.1038/cddis.2013.386 DB - PRIME DP - Unbound Medicine ER -