Multiple Functions of Nm23-H1 Are Regulated by Oxido-Reduction System

Nucleoside diphosphate kinase (NDPK, Nm23), a housekeeping enzyme, is known to be a multifunctional protein, acting as a metastasis suppressor, transactivation activity on c-myc, and regulating endocytosis. The cellular mechanisms regulating Nm23 functions are poorly understood. In this study, we identified the modifications and interacting proteins of Nm23-H1 in response to oxidative stress. We found that Cys109 in Nm23-H1 is oxidized to various oxidation states including intra- and inter-disulfide crosslinks, glutathionylation, and sulfonic acid formation in response to H2O2 treatment both in vivo and in vitro. The cross-linking sites and modifications of oxidized Nm23-H1 were identified by peptide sequencing using UPLC-ESI-q-TOF tandem MS. Glutathionylation and oxidation of Cys109 inhibited the NDPK enzymatic activity of Nm23-H1. We also found that thioredoxin reductase 1 (TrxR1) is an interacting protein of Nm23-H1, and it binds specifically to oxidized Nm23-H1. Oxidized Nm23 is a substrate of NADPH-TrxR1-thioredoxin shuttle system, and the disulfide crosslinking is reversibly reduced and the enzymatic activity is recovered by this system. Oxidation of Cys109 in Nm23-H1 inhibited its metastatic suppressor activity as well as the enzymatic activities. The mutant, Nm23-H1 C109A, retained both the enzymatic and metastasis suppressor activities under oxidative stress. This suggests that key enzymatic and metastasis suppressor functions of Nm23-H1 are regulated by oxido-reduction of its Cys109

Eutrophication and succession of phytoplankton in reservoir of Korea - monthly variations of plankton community in Lake Soyang

The community of plankton and the environmental factors were investigated in Lake Soyang from January to July 1994. The relationship between transparency and biovolume of phytoplankton was negatively correlated. Phytoplankton dominants in Lake Soyang were Anabaena spp., Microcystis aeruginosa, Asterionella formosa, Asterionella gracillima Melosira distans, Synedra acus, and Asterococcus limneticus, Zooplankton dominants were Polyarthra spp., Keratella spp., Asplanchna placentula, Bosmina coregoni, and Daphnia longispona. Phytoplankton and zooplankton were clearly related each other with respect to biovolume, not to numbers. Microcystis aeruginosa rapidly increased and Daphnia longirostris disappeared in July, because Microcystis aeruginosa secret toxic substances to Daphnia longirostris. Transparency decreased from January to June, but increased in July. The highest number of phytoplankton was obserbed in April, and one month later, the zooplankton reached a maximal level in population density, implicating that spring bloom of phytoplankton was good feeding condition for zooplankton.Article信州大学理学部附属諏訪臨湖実験所報告 9: 175-186(1995)departmental bulletin pape

USP15 regulates dynamic protein-protein interactions of the spliceosome through deubiquitination of PRP31.

Post-translational modifications contribute to the spliceosome dynamics by facilitating the physical rearrangements of the spliceosome. Here, we report USP15, a deubiquitinating enzyme, as a regulator of protein-protein interactions for the spliceosome dynamics. We show that PRP31, a component of U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and deubiquitinated by USP15 and its substrate targeting factor SART3. USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3. The ubiquitination and deubiquitination status of PRP31 regulates its interaction with the U5 snRNP component PRP8, which is required for the efficient splicing of chromosome segregation related genes, probably by stabilizing the U4/U6.U5 tri-snRNP complex. Collectively, our data suggest that USP15 plays a key role in the regulation of dynamic protein-protein interactions of the spliceosome

Bloody nipple discharge in an infant

Although milky nipple discharge appears frequently in infants, bloody nipple discharge is a very rare finding. We experienced a 4-month-old, breast-fed infant who showed bilateral bloody nipple discharge with no signs of infection, engorgement, or hypertrophy. The infant's hormonal examination and coagulation tests were normal, and an ultrasound examination revealed mammary duct ectasia. The symptoms resolved spontaneously within 6 weeks without any specific treatment, except that we advised the mother to refrain from taking herbal medicine. Since no such case has been previously reported in Korea, we present this case with a brief review of the literature

Cry1 expression during postnatal development is critical for the establishment of normal circadian period

The mammalian circadian system generates an approximate 24-h rhythm through a complex autoregulatory feedback loop. Four genes, Period1 (Per1), Period2 (Per2), Cryptochrome1 (Cry1), and Cryptochrome2 (Cry2), regulate the negative feedback within this loop. Although these proteins have distinct roles within the core circadian mechanism, their individual functions are poorly understood. Here, we used a tetracycline trans-activator system (tTA) to examine the role of transcriptional oscillations in Cry1 and Cry2 in the persistence of circadian activity rhythms. We demonstrate that rhythmic Cry1 expression is an important regulator of circadian period. We then define a critical period from birth to postnatal day 45 (PN45) where the level of Cry1 expression is critical for setting the endogenous free running period in the adult animal. Moreover, we show that, although rhythmic Cry1 expression is important, in animals with disrupted circadian rhythms overexpression of Cry1 is sufficient to restore normal behavioral periodicity. These findings provide new insights into the roles of the Cryptochrome proteins in circadian rhythmicity and further our understanding of the mammalian circadian clock

Correction to: Circulating exosomes from patients with systemic lupus erythematosus induce an proinflammatory immune response

An amendment to this paper has been published and can be accessed via the original article

Characteristics of interval gastric neoplasms detected within two years after negative screening endoscopy among Koreans

Background In Korea, where gastric cancer is highly prevalent, biennial endoscopy is recommended among individuals over 40. Even under regular screening, some are still diagnosed at advanced stages. We aimed to identify characteristics of interval gastric neoplasms (IGNs) with rapid progression. Results Newly-diagnosed gastric neoplasms detected in screening endoscopy between January 2004 and May 2016 were reviewed. Among them, those who had previous endoscopy within 2 years were enrolled. Endoscopic findings, family history of gastric cancer, smoking, and H. pylori status were analysed. Totally, 297 IGN cases were enrolled. Among them, 246 were endoscopically treatable IGN (ET-IGN) and 51 were endoscopically untreatable IGNs (EUT-IGN) by the expanded criteria for endoscopic submucosal dissection. Among EUT-IGNs, 78% were undifferentiated cancers (40/51) and 33% showed submucosal invasion (13/40). They were median 2.0 cm in size and more commonly located in the proximal stomach than ET-IGNs (70.6% vs. 41.9%, p < 0.001). EUT-IGN was independently related with age < 60 (OR, 2.09; 95%CI, 1.03–4.26, p = 0.042), H. pylori (OR, 2.81; 95%CI, 1.20–6.63, p = 0.018), and absent/mild gastric atrophy (OR, 2.67; 95%CI, 1.25–5.72, p = 0.011). Overall and disease-specific survival were not significantly different between the two groups, however EUT-IGN tended to have short disease-specific survival (overall survival, p = 0.143; disease-specific survival, p = 0.083). Conclusions Uniform screening endoscopy with two-year interval seems not enough for rapid-growing gastric neoplasms, such as undifferentiated cancers. They tended to develop in adults younger than 60 with H. pylori infection without severe gastric atrophy. More meticulous screening, especially for proximal lesions is warranted for adults younger than 60 with H. pylori infection before development of gastric atrophy

β-Lapachone Significantly Increases the Effect of Ionizing Radiation to Cause Mitochondrial Apoptosis via JNK Activation in Cancer Cells

β-lapachone (β-lap), has been known to cause NQO1-dependnet death in cancer cells and sensitize cancer cells to ionizing radiation (IR). We investigated the mechanisms underlying the radiosensitization caused by β-lap. cells induced ROS generation, triggered ER stress and stimulated activation of ERK and JNK. Inhibition of ROS generation by NAC effectively attenuated the activation of ERK and JNK, induction of ER stress, and subsequent apoptosis. Importantly, inhibition of ERK abolished ROS generation and ER stress, whereas inhibition of JNK did not, indicating that positive feedback regulation between ERK activation and ROS generation triggers ER stress in response to combined treatment. Furthermore, prevention of ER stress completely blocked combination treatment-induced JNK activation and subsequent apoptotic cell death. In addition, combined treatment efficiently induced the mitochondrial translocation of cleaved Bax, disrupted mitochondrial membrane potential, and the nuclear translocation of AIF, all of which were efficiently blocked by a JNK inhibitor. Caspases 3, 8 and 9 were activated by combined treatment but inhibition of these caspases did not abolish apoptosis indicating caspase activation played a minor role in the induction of apoptosis. cells are treated with combination of IR and β-lap, positive feedback regulation between ERK and ROS leads to ER stress causing JNK activation and mitochondrial translocation of cleaved Bax. The resultant decrease in mitochondrial membrane leads to translocation of AIF and apoptosis