SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction

The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.     

A high C/O ratio and weak thermal inversion in the atmosphere of exoplanet WASP-12b

The carbon-to-oxygen ratio (C/O) in a planet provides critical information about its primordial origins and subsequent evolution. A primordial C/O greater than 0.8 causes a carbide-dominated interior, as opposed to the silicate-dominated composition found on Earth; the atmosphere can also differ from those in the Solar System. The solar C/O is 0.54 (ref. 3). Here we report an analysis of dayside multi-wavelength photometry of the transiting hot-Jupiter WASP-12b (ref. 6) that reveals C/O?≥?1 in its atmosphere. The atmosphere is abundant in CO. It is depleted in water vapour and enhanced in methane, each by more than two orders of magnitude compared to a solar-abundance chemical-equilibrium model at the expected temperatures. We also find that the extremely irradiated atmosphere (T?>?2,500?K) of WASP-12b lacks a prominent thermal inversion (or stratosphere) and has very efficient day-night energy circulation. The absence of a strong thermal inversion is in stark contrast to theoretical predictions for the most highly irradiated hot-Jupiter atmospheres.     

An ancient recipe for flood-basalt genesis

Large outpourings of basaltic lava have punctuated geological time, but the mechanisms responsible for the generation of such extraordinary volumes of melt are not well known. Recent geochemical evidence suggests that an early-formed reservoir may have survived in the Earth's mantle for about 4.5 billion years (ref. 2), and melts of this reservoir contributed to the flood basalt emplaced on Baffin Island about 60 million years ago. However, the volume of this ancient mantle domain and whether it has contributed to other flood basalts is not known. Here we show that basalts from the largest volcanic event in geologic history--the Ontong Java plateau--also exhibit the isotopic and trace element signatures proposed for the early-Earth reservoir. Together with the Ontong Java plateau, we suggest that six of the largest volcanic events that erupted in the past 250 million years derive from the oldest terrestrial mantle reservoir. The association of these large volcanic events with an ancient primitive mantle source suggests that its unique geochemical characteristics--it is both hotter (it has greater abundances of the radioactive heat-producing elements) and more fertile than depleted mantle reservoirs-may strongly affect the generation of flood basalts.     

Eocene global warming events driven by ventilation of oceanic dissolved organic carbon

'Hyperthermals' are intervals of rapid, pronounced global warming known from six episodes within the Palaeocene and Eocene epochs (～65-34 million years (Myr) ago). The most extreme hyperthermal was the ～170 thousand year (kyr) interval of 5-7 °C global warming during the Palaeocene-Eocene Thermal Maximum (PETM, 56?Myr ago). The PETM is widely attributed to massive release of greenhouse gases from buried sedimentary carbon reservoirs, and other, comparatively modest, hyperthermals have also been linked to the release of sedimentary carbon. Here we show, using new 2.4-Myr-long Eocene deep ocean records, that the comparatively modest hyperthermals are much more numerous than previously documented, paced by the eccentricity of Earth's orbit and have shorter durations (～40?kyr) and more rapid recovery phases than the PETM. These findings point to the operation of fundamentally different forcing and feedback mechanisms than for the PETM, involving redistribution of carbon among Earth's readily exchangeable surface reservoirs rather than carbon exhumation from, and subsequent burial back into, the sedimentary reservoir. Specifically, we interpret our records to indicate repeated, large-scale releases of dissolved organic carbon (at least 1,600 gigatonnes) from the ocean by ventilation (strengthened oxidation) of the ocean interior. The rapid recovery of the carbon cycle following each Eocene hyperthermal strongly suggests that carbon was re-sequestered by the ocean, rather than the much slower process of silicate rock weathering proposed for the PETM. Our findings suggest that these pronounced climate warming events were driven not by repeated releases of carbon from buried sedimentary sources, but, rather, by patterns of surficial carbon redistribution familiar from younger intervals of Earth history.     

Exploration of opportunity costs and consideration exploration of opportunity costs and consideration for future generations: Two lasting contributions to systems thinking

In his numerous writings C. West Churchman has shown how the systems approach can be used to secure improvements in the human condition. Specifically one must think holistically. Two concepts—exploration of opportunity costs and consideration for future generations—underline whole systems thinking. The author argues based on his own experience that these tools of the human intellect are among the most lasting contributions Churchman has made to systems thinking.