Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase

The target of rapamycin (TOR) plays a central role in eukaryotic cell growth control. With prevalent hyperactivation of the mammalian TOR (mTOR) pathway in human cancers, strategies to enhance TOR pathway inhibition are needed. We used a yeast-based screen to identify small-molecule enhancers of rapamycin (SMERs) and discovered an inhibitor (SMER3) of the Skp1-Cullin-F-box (SCF)^(Met30) ubiquitin ligase, a member of the SCF E3-ligase family, which regulates diverse cellular processes including transcription, cell-cycle control and immune response. We show here that SMER3 inhibits SCF^(Met30) in vivo and in vitro, but not the closely related SCF^(Cdc4). Furthermore, we demonstrate that SMER3 diminishes binding of the F-box subunit Met30 to the SCF core complex in vivo and show evidence for SMER3 directly binding to Met30. Our results show that there is no fundamental barrier to obtaining specific inhibitors to modulate function of individual SCF complexes

An analysis of potential controls on long-term 137Cs accumulation in the sediments of UK lakes

137 Cs has been utilised extensively to investigate catchment sediment dynamics. Its activity can be indicative of sediment derived from surface sources, and its inventory in deposited sediments reflects local fallout, radioactive decay, sediment accumulation and sediment source. Lakes represent ideal depositional environments for the reconstruction of historical sediment dynamics. In the UK, depth profiles and inventories of 137 Cs in lake cores have been investigated in a large number of catchments, but no study has synthesised all of these data to identify national spatial trends. The aim of this study was therefore to determine what can be learnt from 137 Cs inventories and profiles from UK lakes. Analysis revealed that local reference fallout, the rate of linear sediment accumulation (cm year −1 ) and the lake area:catchment area ratio, are the most important factors that control lake 137 Cs inventories. Delivery of mobile 137 Cs to the lake shortly after fallout, dissolved in runoff, or associated with mobilised sediment in transit from the source to the lake, is also likely a major control on inventories, especially on down-core profiles and peak activities. It is possible that dissolved 137 Cs inputs remain important controls on activities in recently deposited sediments, as they are often higher than potential contributing catchment sediment sources. It is also likely that finer particle-size distributions in lake-bed sediments, compared with source materials, increase both activities and inventories. Uncertainties are associated with patterns of sediment deposition on the lake bed and the estimation of local reference fallout, and lakes with low catchment-derived 137 Cs inputs potentially have a comparable or lower inventory than calculated from the estimated reference fallout. Lakes with multiple inlet tributaries and poor mixing of inflows, or an irregular bed shape divided by ridges and depressions, are also likely to display considerable variability in sediment-associated 137 Cs deposition. Despite these uncertainties, 137 Cs depth profiles provide valuable information on sediment sources and dynamics when interpreted carefully in the context of other UK lakes, and in relation to the corresponding catchment and lake characteristics. Several distinctive down-core profiles and inventories reported here yielded valuable insights into catchment sediment dynamics