Serine/threonine kinase 17A is a novel p53 target gene and modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells.

Testicular cancer is highly curable with cisplatin-based therapy, and testicular cancer-derived human embryonal carcinoma (EC) cells undergo a p53-dominant transcriptional response to cisplatin. In this study, we have discovered that a poorly characterized member of the death-associated protein family of serine/threonine kinases, STK17A (also called DRAK1), is a novel p53 target gene. Cisplatin-mediated induction of STK17A in the EC cell line NT2/D1 was prevented with p53 siRNA. Furthermore, STK17A was induced with cisplatin in HCT116 and MCF10A cells but to a much lesser extent in isogenic p53-suppressed cells. A functional p53 response element that binds endogenous p53 in a cisplatin-dependent manner was identified 5 kb upstream of the first coding exon of STK17A. STK17A is not present in the mouse genome, but the closely related gene STK17B is induced with cisplatin in mouse NIH3T3 cells, although this induction is p53-independent. Interestingly, in human cells containing both STK17A and STK17B, only STK17A is induced with cisplatin. Knockdown of STK17A conferred resistance to cisplatin-induced growth suppression and apoptotic cell death in EC cells. This was associated with the up-regulation of detoxifying and antioxidant genes, including metallothioneins MT1H, MT1M, and MT1X that have previously been implicated in cisplatin resistance. In addition, knockdown of STK17A resulted in decreased cellular reactive oxygen species, whereas STK17A overexpression increased reactive oxygen species. In summary, we have identified STK17A as a novel direct target of p53 and a modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells.

Repeat disturbances have cumulative impacts on stream communities.

Climate change has altered disturbance regimes in many ecosystems, and predictions show that these trends are likely to continue. The frequency of disturbance events plays a particularly important role in communities by selecting for disturbance-tolerant taxa.However, ecologists have yet to disentangle the influence of disturbance frequency per se and time since last disturbance, because more frequently disturbed systems have also usually been disturbed more recently. Our understanding of the effects of repeated disturbances is therefore confounded by differences in successional processes.We used in-situ stream mesocosms to isolate and examine the effect of disturbance frequency on community composition. We applied substrate moving disturbances at five frequencies, with the last disturbance occurring on the same day across all treatments. Communities were then sampled after a recovery period of 9 days.Macroinvertebrate community composition reflected the gradient of disturbance frequency driven by differential vulnerability of taxa to disturbance. Diversity metrics, including family-level richness, decreased, reflecting a likely loss of functional diversity with increasing disturbance frequency. In contrast, overall abundance was unaffected by disturbance frequency as rapid recovery of the dominant taxon compensated for strong negative responses of disturbance-vulnerable taxa.We show that cumulative effects of repeated disturbances-not just the time communities have had to recover before sampling-alter communities, especially by disproportionately affecting rare taxa. Thus, the timing of past disturbances can have knock-on effects that determine how a system will respond to further change.