Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities.

Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens. We show that a weak allele of axin, which deregulates Wg signaling and increases cell proliferation without obvious effects on cell fate specification, significantly alters metabolic gene expression, causes hypersensitivity to metabolic stress induced by fasting, and induces synergistic apoptosis with mutation of fly Rb ortholog, rbf. Furthermore, hyperactivation of Wg signaling by other components of the Wg pathway also induces synergistic apoptosis with rbf. We show that hyperactivated Wg signaling significantly increases TORC1 activity and induces excessive energy stress with rbf mutation. Inhibition of TORC1 activity significantly suppressed synergistic cell death induced by hyperactivated Wg signaling and rbf inactivation, which is correlated with decreased energy stress and decreased induction of apoptotic regulator expression. Finally the synthetic lethality between Rb and deregulated Wnt signaling is conserved in mammalian cells and that inactivation of Rb and APC induces synergistic cell death through a similar mechanism. These results suggest that elevated TORC1 activity and metabolic stress underpin the evolutionarily conserved synthetic lethal interaction between hyperactivated Wnt signaling and inactivated Rb tumor suppressor.

More than 500 million Chinese urban residents (14% of the global urban population) are imperiled by fine particulate hazard.

China's urbanization and the subsequent public vulnerability to degenerated environment is important to global public health. Among the environmental problems, fine particulate (PM2.5) pollution has become a serious hazard in rapidly urbanizing China. However, quantitative information remains inadequate. We thus collected PM2.5 concentrations and population census records, to illustrate the spatial patterns and changes in the PM2.5 hazard levels in China, and to quantify public vulnerability to the hazard during 2000-2010, following the air quality standards of World Health Organization. We found that 28% (2.72 million km2) of China's territory, including 78% of cities (154 cities) with a population of >1 million, was exposed to PM2.5 hazard in 2010; a 15% increase (1.47 million km2) from 2000 to 2010. The hazards potentially impacted the health of 72% of the total population (942 million) in 2010, including 70% of the young (206 million) and 76% of the old (71 million). This was a significant increase from the 42% of total the population (279 million) exposed in 2000. Of the total urban residents, 76% (501 million) were affected in 2010. Along with PM2.5 concentration increase, massive number of rural to urban migration also contributed greatly to China's urban public health vulnerability.

Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly.

Biogenesis of high-density lipoproteins (HDL) is coupled to the transmembrane protein, ATP-binding cassette transporter A1 (ABCA1), which transports phospholipid (PL) from the inner to the outer membrane monolayer. Using a combination of computational and experimental approaches, we show that increased outer lipid monolayer surface density, driven by excess PL or membrane insertion of amphipathic helices, results in pleating of the outer monolayer to form membrane-attached discoidal bilayers. Apolipoprotein (apo)A-I accelerates and stabilizes the pleats. In the absence of apoA-I, pleats collapse to form vesicles. These results mimic cells overexpressing ABCA1 that, in the absence of apoA-I, form and release vesicles. We conclude that the basic driving force for nascent discoidal HDL assembly is a PL pump-induced surface density increase that produces lipid monolayer pleating. We then argue that ABCA1 forms an extracellular reservoir containing an isolated pressurized lipid monolayer decoupled from the transbilayer density buffering of cholesterol.