Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers, in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibiting the † To whom correspondence should be addressed. david.tuveson@cancer.org.uk.

Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occured in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans-side of the Golgi apparatus, the ‘TOR-autophagy spatial coupling compartment’ (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid- and Rag guanosine triphosphatase (GTPase)-dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC-formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells’ catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins.

Autosomal recessive primary microcephaly (MCPH) is characterised by a significant reduction in prenatal human brain growth, without alteration of cerebral architecture. The genetic aetiology of MCPH is bi-allelic mutations in genes coding for a subset of centrosomal proteins1-10. While at least three of these proteins have been implicated in centrosome duplication11, the nature of centrosome dysfunction that underlies the neurodevelopmental defect in MCPH is unclear. Here we report a homozygous MCPH-causing mutation in the human CEP63 gene. CEP63 forms a complex with another MCPH protein, CEP152, a conserved centrosome duplication factor12-15. Together, they are essential for maintaining normal centrosome numbers in cells. Using super-resolution microscopy we find that CEP63 and CEP152 co-localise in a discrete ring around the proximal end of the parental centriole, a pattern specifically disrupted in CEP63-deficient patient-derived cells. This work suggests that the CEP152-CEP63 ring-like structure ensures normal neurodevelopment and its impairment particularly affects human cerebral cortex growth.

Many copies of mammalian mitochondrial DNA contain a short triple-stranded region, or displacement loop (D-loop), in the major noncoding region. In the 35 years since their discovery, no function has been assigned to mitochondrial D-loops. We purified mitochondrial nucleoprotein complexes from rat liver and identified a previously uncharacterized protein, ATAD3p. Localization studies suggested that human ATAD3 is a component of many, but not all, mitochondrial nucleoids. Gene silencing of ATAD3 by RNA interference altered the structure of mitochondrial nucleoids and led to the dissociation of mitochondrial DNA fragments held together by protein, specifically, ones containing the D-loop region. In vitro, a recombinant fragment of ATAD3p bound to supercoiled DNA molecules that contained a synthetic D-loop, with a marked preference over partially relaxed molecules with a D-loop or supercoiled DNA circles. These results suggest that mitochondrial D-loops serve to recruit ATAD3p for the purpose of forming or segregating mitochondrial nucleoids.

SummaryMyosins are a large superfamily of motor proteins which, in association with actin, are involved in intracellular motile processes. In addition to the conventional myosins involved in muscle contractility, there is, in animal cells, a wide range of unconventional myosins implicated in membrane-associated processes, such as vesicle transport and membrane dynamics. In plant cells, however, very little is known about myosins. We have raised an antibody to the recombinant tail region of Arabidopsis thaliana myosin 1 (a class VIII myosin) and used it in immuno¯uorescence and EM studies on root cells from cress and maize. The plant myosin VIII is found to be concentrated at newly formed cross walls at the stage in which the phragmoplast cytoskeleton has depolymerized and the new cell plate is beginning to mature. These walls are rich in plasmodesmata and we show that they are the regions where the longitudinal actin cables appear to attach. Myosin VIII appears to be localized in these plasmodesmata and we suggest that this protein is involved in maturation of the cell plate and the re-establishment of cytoplasmic actin cables at sites of intercellular communication.