APC/C: current understanding and future perspectives [version 1; peer review: 3 approved]

The separation of sister chromatids at anaphase, which is regulated by an E3 ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC/C), is arguably the most important irrevocable event during the cell cycle. The APC/C and cyclin-dependent kinase 1 (Cdk1) are just two of the many significant cell cycle regulators and exert control through ubiquitylation and phosphorylation, respectively. The temporal and spatial regulation of the APC/C is achieved by multiple mechanisms, including phosphorylation, interaction with the structurally related co-activators Cdc20 and Cdh1, loading of distinct E2 ubiquitin-conjugating enzymes, binding with inhibitors and differential affinities for various substrates. Since the discovery of APC/C 25 years ago, intensive studies have uncovered many aspects of APC/C regulation, but we are still far from a full understanding of this important cellular machinery. Recent high-resolution cryogenic electron microscopy analysis and reconstitution of the APC/C have greatly advanced our understanding of molecular mechanisms underpinning the enzymatic properties of APC/C. In this review, we will examine the historical background and current understanding of APC/C regulation

Active liquid-crystal deflector and lens with Fresnel structure

SPIE OPTO, 2017, San Francisco, California, United StatesGiichi Shibuya, Shohei Yamano, Hiroyuki Yoshida, and Masanori Ozaki "Active liquid-crystal deflector and lens with Fresnel structure", Proc. SPIE 10125, Emerging Liquid Crystal Technologies XII, 101250V (15 February 2017). DOI: https://doi.org/10.1117/12.226111

Targeting of Fzr/Cdh1 for timely activation of the APC/C at the centrosome during mitotic exit.

A multi-subunit ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), regulates critical cellular processes including the cell cycle. To accomplish its diverse functions, APC/C activity must be precisely regulated in time and space. The interphase APC/C activator Fizzy-related (Fzr or Cdh1) is localized at centrosomes in animal cells. However, neither the mechanism of its localization nor its importance is clear. Here we identify the centrosome component Spd2 as a major partner of Fzr in Drosophila. The localization of Fzr to the centriole during interphase depends on direct interaction with Spd2. By generating Spd2 mutants unable to bind Fzr, we show that centrosomal localization of Fzr is essential for optimal APC/C activation towards its centrosomal substrate Aurora A. Finally, we show that Spd2 is also a novel APC/C(Fzr) substrate. Our study is the first to demonstrate the critical importance of distinct subcellular pools of APC/C activators in the spatiotemporal control of APC/C activity.Cancer Research UK (Career Development Fellowship), Biotechnology and Biological Sciences Research Council (project grant), Medical Research Council (project grant), Japan Society for the Promotion of Science (Postdoctoral Fellowship for Research Abroad), European Commission (Marie Skłodowska-Curie actions individual fellowship)This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1260

Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase

SummaryTargeting mitotic exit has been recently proposed as a relevant therapeutic approach against cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essential for anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20 results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects. Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall). This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55α or B55δ regulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells

Clinical study for evaluation of Percutaneous Transhepatic Gallbladder Drainage : PTCD associated with PTGBD

Eight cases of PTGBD were investigated. The average age was 69.3 years, and 6 cases were male and 2 cases were female. There were 6 cases of acute cholecystitis and 2 cases of malignant disease (1 middle bile duct cancer, 1 pancreas head cancer). Before state of PTGBD of these patients, severe cardiac disease and after posterior spinal fixation and other disease were observed. Using PTGBD, pain, fever, and other symptoms had remarkably improved in all patients. In all 6 patients with acute cholecystitis, CRP and leukocyte were significantly decreased as the 2 days after this procedure. PTCD associated with PTGBD was performd in 2 patients with middle or distal obstruction of the common bile duct. The bilirubin decrease rate"b" (b value) was-0.20±0.03 (M±SE) in the PTGBD+PTCD group and-0.096±0.15 (M±SE) in the only PTCD group, with a statistically significant difference (p<0.01). The procedure was effective in reducing jaundice

Plasmodium P-type cyclin CYC3 modulates endomitotic growth during oocyst development in mosquitoes

Cell-cycle progression and cell division in eukaryotes are governed in part by the cyclin family and their regulation of cyclin-dependent kinases (CDKs). Cyclins are very well characterised in model systems such as yeast and human cells, but surprisingly little is known about their number and role in Plasmodium, the unicellular protozoan parasite that causes malaria. Malaria parasite cell division and proliferation differs from that of many eukaryotes. During its life cycle it undergoes two types of mitosis: endomitosis in asexual stages and an extremely rapid mitotic process during male gametogenesis. Both schizogony (producing merozoites) in host liver and red blood cells, and sporogony (producing sporozoites) in the mosquito vector, are endomitotic with repeated nuclear replication, without chromosome condensation, before cell division. The role of specific cyclins during Plasmodium cell proliferation was unknown. We show here that the Plasmodium genome contains only three cyclin genes, representing an unusual repertoire of cyclin classes. Expression and reverse genetic analyses of the single Plant (P)-type cyclin, CYC3, in the rodent malaria parasite, Plasmodium berghei, revealed a cytoplasmic and nuclear location of the GFP-tagged protein throughout the lifecycle. Deletion of cyc3 resulted in defects in size, number and growth of oocysts, with abnormalities in budding and sporozoite formation. Furthermore, global transcript analysis of the cyc3-deleted and wild type parasites at gametocyte and ookinete stages identified differentially expressed genes required for signalling, invasion and oocyst development. Collectively these data suggest that cyc3 modulates oocyst endomitotic development in Plasmodium berghei

Zigzag-Elongated Fused π-Electronic Core: A Molecular Design Strategy to Maximize Charge-Carrier Mobility

Printed and flexible electronics requires solution‐processable organic semiconductors with a carrier mobility (μ) of ≈10 cm2 V−1 s−1 as well as high chemical and thermal durability. In this study, chryseno[2,1‐b:8,7‐b′]dithiophene (ChDT) and its derivatives, which have a zigzag‐elongated fused π‐electronic core (π‐core) and a peculiar highest occupied molecular orbital (HOMO) configuration, are reported as materials with conceptually new semiconducting π‐cores. ChDT and its derivatives are prepared by a versatile synthetic procedure. A comprehensive investigation reveals that the ChDT π‐core exhibits increasing structural stability in the bulk crystal phase, and that it is unaffected by a variation of the transfer integral, induced by the perpetual molecular motion of organic materials owing to the combination of its molecular shape and its particular HOMO configuration. Notably, ChDT derivatives exhibit excellent chemical and thermal stability, high charge‐carrier mobility under ambient conditions (μ ≤ 10 cm2 V−1 s−1), and a crystal phase that is highly stable, even at temperatures above 250 °C