ALBERT

Description: 〈p〉Stabilization of the MYC oncoprotein by KRAS signaling critically promotes the growth of pancreatic ductal adenocarcinoma (PDAC). Thus, understanding how MYC protein stability is regulated may lead to effective therapies. Here, we used a previously developed, flow cytometry–based assay that screened a library of 〉800 protein kinase inhibitors and identified compounds that promoted either the stability or degradation of MYC in a KRAS-mutant PDAC cell line. We validated compounds that stabilized or destabilized MYC and then focused on one compound, UNC10112785, that induced the substantial loss of MYC protein in both two-dimensional (2D) and 3D cell cultures. We determined that this compound is a potent CDK9 inhibitor with a previously uncharacterized scaffold, caused MYC loss through both transcriptional and posttranslational mechanisms, and suppresses PDAC anchorage-dependent and anchorage-independent growth. We discovered that CDK9 enhanced MYC protein stability through a previously unknown, KRAS-independent mechanism involving direct phosphorylation of MYC at Ser〈sup〉62〈/sup〉. Our study thus not only identifies a potential therapeutic target for patients with KRAS-mutant PDAC but also presents the application of a screening strategy that can be more broadly adapted to identify regulators of protein stability.〈/p〉

Description: We investigate the contribution of oceanic methyl iodide (CH3I) to the stratospheric iodine budget. Based on CH3I measurements from three tropical ship campaigns and the Lagrangian transport model FLEXPART, we provide a detailed analysis of CH3I transport from the ocean surface to the cold point in the upper tropical tropopause layer (TTL). While average oceanic emissions differ by less than 50% from campaign to campaign, the measurements show much stronger variations within each campaign. A positive correlation between the oceanic CH3I emissions and the efficiency of CH3I troposphere–stratosphere transport has been identified for some cruise sections. The mechanism of strong horizontal surface winds triggering large emissions on the one hand and being associated with tropical convective systems, such as developing typhoons, on the other hand, could explain the identified correlations. As a result of the simultaneous occurrence of large CH3I emissions and strong vertical uplift, localized maximum mixing ratios of 0.6 ppt CH3I at the cold point have been determined for observed peak emissions during the SHIVA (Stratospheric Ozone: Halogen Impacts in a Varying Atmosphere)-Sonne research vessel campaign in the coastal western Pacific. The other two campaigns give considerably smaller maxima of 0.1 ppt CH3I in the open western Pacific and 0.03 ppt in the coastal eastern Atlantic. In order to assess the representativeness of the large local mixing ratios, we use climatological emission scenarios to derive global upper air estimates of CH3I abundances. The model results are compared with available upper air measurements, including data from the recent ATTREX and HIPPO2 aircraft campaigns. In the eastern Pacific region, the location of the available measurement campaigns in the upper TTL, the comparisons give a good agreement, indicating that around 0.01 to 0.02 ppt of CH3I enter the stratosphere. However, other tropical regions that are subject to stronger convective activity show larger CH3I entrainment, e.g., 0.08 ppt in the western Pacific. Overall our model results give a tropical contribution of 0.04 ppt CH3I to the stratospheric iodine budget. The strong variations in the geographical distribution of CH3I entrainment suggest that currently available upper air measurements are not representative of global estimates and further campaigns will be necessary in order to better understand the CH3I contribution to stratospheric iodine.