Unknown

Dataset Information

0

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.


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 (?IR)-induced apoptosis, driving them into senescence even in the absence of ?IR. 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.

SUBMITTER: Neise D 

PROVIDER: S-EPMC3920941 | BioStudies | 2013-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

2013-01-01 | S-EPMC3573779 | BioStudies
2020-01-01 | S-EPMC7321696 | BioStudies
1000-01-01 | S-EPMC3908613 | BioStudies
2007-01-01 | S-EPMC1698666 | BioStudies
2013-01-01 | S-EPMC3596281 | BioStudies
2011-01-01 | S-EPMC3149304 | BioStudies
2007-01-01 | S-EPMC3634365 | BioStudies
2013-01-01 | S-EPMC3712578 | BioStudies
2017-01-01 | S-EPMC6342201 | BioStudies
2017-01-01 | S-EPMC5548783 | BioStudies