Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-β1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3β (GSK3β), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-β1-induced EMT and metastasis of basal-like breast cancers.

This paper develops econometric methods for inference and prediction in quantile regression (QR) allowing for persistent predictors. Conventional QR econometric techniques lose their validity when predictors are highly persistent. I adopt and extend a methodology called IVX …ltering (Magdalinos and Phillips, 2009) that is designed to handle predictor variables with various degrees of persistence. The proposed IVX-QR methods correct the distortion arising from persistent multivariate predictors while preserving discriminatory power. Simulations con…rm that IVX-QR methods inherit the robust properties of QR. These methods are employed to examine the predictability of US stock returns at various quantile levels.

Transforming growth factor (TGF)-b, a pivotal cytokine involved in a variety of cellular functions, transmits signals through Smad-dependent canonical and Smad-independent noncanonical pathways. In contrast to the canonical TGF-b pathway, it is unknown how noncanonical TGF-b pathways are negatively regulated. Here we demonstrate that the inhibitory Smad Smad6, but not Smad7, negatively regulates TGF-b1-induced activation of the TRAF6-TAK1-p38 MAPK/JNK pathway, a noncanonical TGF-b pathway. TGF-b1-induced Smad6 abolishes K63-linked polyubiquitination of TRAF6 by recruiting the A20 deubiquitinating enzyme in AML-12 mouse liver cells and primary hepatocytes. In addition, the knockdown of Smad6 or A20 in an animal model or cell culture system maintains TAK1 and p38 MAPK/JNK phosphorylation and increases apoptosis, emphasizing the crucial role of the Smad6-A20 axis in negative regulation of the TGF-b1-TRAF6-TAK1-p38 MAPK/JNK pathway. Therefore, our findings provide insight into the molecular mechanisms underlying negative regulation of noncanonical TGF-b pathways.

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We synthesized a novel fully conjugated block copolymer, P3, in which a wide-band gap donor block (P1) was connected to a narrow-band gap acceptor block (P2). As P3 contains P1 block with a wide bandgap and P2 block with a narrow bandgap, it exhibits a very wide complementary absorption. Transient photoluminescence measurement using P3 dilute solution demonstrated intramolecular charge transfer between the P1 block and the P2 block, which was not observed in a P1/P2 blend solution. A P3 thin film showed complete PL quenching because the photoinduced inter-/intramolecular charge transfer states were effectively formed. This phenomenon can play an important role in the photovoltaic properties of P3-based polymer solar cells. A single active material polymer solar cell (SAMPSC) fabricated from P3 alone exhibited a high power conversion efficiency (PCE) of 3.87% with a high open-circuit voltage of 0.93 V and a short-circuit current of 8.26 mA/cm, demonstrating a much better performance than a binary P1-/P2-based polymer solar cell (PCE = 1.14%). This result facilitates the possible improvement of the photovoltaic performance of SAMPSCs by inducing favorable nanophase segregation between p- and n blocks. In addition, owing to the high morphological stability of the block copolymer, excellent shelf-life was observed in a P3-based SAMPSC compared with a P1/P2-based PSC.