Summary Bim is a proapoptotic BH3-only Bcl-2 family member. In response to death stimuli, Bim dissociates from the dynein light chain 1 (DYNLL1/LC8), where it is inactive, and can then initiate Bax/Bak-mediated mitochondria-dependent apoptosis. We found that Bim depletion increases autophagosome synthesis in cells and in vivo, and this effect is inhibited by overexpression of cell death-deficient Bim. Bim inhibits autophagy by interacting with Beclin 1, an autophagy regulator, and this interaction is facilitated by LC8. Bim bridges the Beclin 1-LC8 interaction and thereby inhibits autophagy by mislocalizing Beclin 1 to the dynein motor complex. Starvation, an autophagic stimulus, induces Bim phosphorylation, which abrogates LC8 binding to Bim, leading to dissociation of Bim and Beclin 1. Our data suggest that Bim switches locations between apoptosis-inactive/autophagy-inhibitory and apoptosis-active/autophagy-permissive sites.

Autophagy is an intracellular degradation process responsible for the clearance of most long-lived proteins and organelles. Cytoplasmic components are enclosed by double-membrane autophagosomes, which subsequently fuse with lysosomes for degradation. Autophagy dysfunction may contribute to the pathology of various neurodegenerative disorders, which manifest abnormal protein accumulation. As autophagy induction enhances the clearance of aggregate-prone intracytoplasmic proteins that cause neurodegeneration (like mutant huntingtin, tau and ataxin 3) and confers cytoprotective roles in cell and animal models, upregulating autophagy may be a tractable therapeutic strategy for diseases caused by such proteins. Here, we will review the molecular machinery of autophagy and its role in neurodegenerative diseases. Drugs and associated signalling pathways that may be targeted for pharmacological induction of autophagy will also be discussed.

The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. This system is responsive to multiple external triggers including temperature, pH and the addition of a competitive guest. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) as a thermoresponsive block and poly(dimethylaminoethylmethacrylate) (PDMAEMA) as a pH-responsive block. Moreover, encapsulation and controlled drug release was demonstrated with this system using the chemotherapeutic drug doxorubicin (DOX). This triple stimuli-responsive DHBC micelle system represents an evolution over conventional double stimuli-responsive covalent diblock copolymer systems and displayed a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micellar nanocontainers.

Autophagy, a major clearance route for many long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus is an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti-Myc strategies and autophagy will be important for development of effective therapy. Here, we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of c-Jun N-terminal kinase 1 (JNK1) and B-cell lymphoma 2 (Bcl2) phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy.

PPCT, AMYY and GS performed the experiments; PPCT and AMYY analysed the data; PPCT designed the research study and wrote the paper; MBQ and PB contributed to study design and essential rea-

The keloid fibroblast (KF) is known to have higher proliferative capacity than normal dermal fibroblast (NF). Metallothionein (MT), a metal-binding protein, has been reported to promote cell proliferation. In this study, we evaluated the expression of MT isoforms at the mRNA level in fetal bovine serum (FBS)-stimulated proliferating KF. Although the morphological appearance of NF and KF was similar when viewed under light, confocal and transmission electron microscopy, there was surprisingly a generally lower expression of MT isoforms in KF when compared with NF and also reduced MT staining in dermal fibroblasts of keloids as opposed to normal skin. Primary cultures of KF grown in 5% FBS or 10% FBS compared to without FBS demonstrated significantly higher proliferative activity and more abundant deposition of collagen. Contrary to expectation, MT-1A, -1F, -1G, -1X and -2A isoforms were significantly down-regulated in proliferating KF. Moreover, stimulating KF with TGF β1, which is known to promote collagen synthesis and keloid formation, increased expression of Collagen 1A and 3A genes accompanied by reduction in MT-2A gene expression. Furthermore, down-regulation of the MT-2A gene in proliferating KF by siRNA-mediated silencing enhanced cell proliferation with concomitant up-regulation of the NF-κB gene and 10 of 13 other NF-κB pathway-related genes analysed but no alteration of the Collagen 1 and Collagen 3 gene expression. It would appear that down-regulation of MT isoforms in proliferating KF, in particular MT-2A, enhances keloidogenesis with the possible involvement of the NF-κB signalling pathway.