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971.
Phosphoinositide 3-kinases (PI3Ks) and Ras and Rho family small GTPases are key regulators of cell polarization, motility, and chemotaxis. They influence each other's activities by direct and indirect feedback processes that are only partially understood. Here, we show that 21 small GTPase homologs activate PI3K. Using a microscopy-based binding assay, we show that K-Ras, H-Ras, and five homologous Ras family small GTPases function upstream of PI3K by directly binding the PI3K catalytic subunit, p110. In contrast, several Rho family small GTPases activated PI3K by an indirect cooperative positive feedback that required a combination of Rac, CDC42, and RhoG small GTPase activities. Thus, a distributed network of Ras and Rho family small GTPases induces and reinforces PI3K activity, explaining past challenges to elucidate the specific relevance of different small GTPases in regulating PI3K and controlling cell polarization and chemotaxis. 相似文献
972.
Takahashi A Imai Y Yamakoshi K Kuninaka S Ohtani N Yoshimoto S Hori S Tachibana M Anderton E Takeuchi T Shinkai Y Peters G Saya H Hara E 《Molecular cell》2012,45(1):123-131
Both the DNA damage response (DDR) and epigenetic mechanisms play key roles in the implementation of senescent phenotypes, but very little is known about how these two mechanisms are integrated to establish senescence-associated gene expression. Here we show that, in senescent cells, the DDR induces proteasomal degradation of G9a and GLP, major histone H3K9 mono- and dimethyltransferases, through Cdc14B- and p21(Waf1/Cip1)-dependent activation of APC/C(Cdh1) ubiquitin ligase, thereby causing a global decrease in H3K9 dimethylation, an epigenetic mark for euchromatic gene silencing. Interestingly, induction of IL-6 and IL-8, major players of the senescence-associated secretory phenotype (SASP), correlated with a decline of H3K9 dimethylation around the respective gene promoters and knockdown of Cdh1 abolished IL-6/IL-8 expression in senescent cells, suggesting that the APC/C(Cdh1)-G9a/GLP axis plays crucial roles in aspects of senescent phenotype. These findings establish a role for APC/C(Cdh1) and reveal how the DDR integrates with epigenetic processes to induce senescence-associated gene expression. 相似文献
973.
Highlights? Activation surge reconstituted in vitro with purified SK and RR ? ADP can be endogenously generated from ATP to stimulate an SK's phosphatase activity ? SK's affinity for ADP governs the switch from the kinase to phosphatase state ? Lid region of SK PhoQ controls its phosphatase activity and surge of RR PhoP 相似文献
974.
The MuS1 gene is highly homologous to many stress-related proteins in plants. Here, we characterized whether a new candidate gene, MuS1, is related to multiple stress tolerance in yeast as it is in plants. Transgenic yeast strain expressing MuS1 were more resistant to hydrogen peroxide, menadione, high salinity, metals (i.e., cadmium, copper, iron, and zinc), ethanol, and lactic acid than wild-type strain transformed with a vector alone. In addition, the alcohol yield of the transgenic yeast strain was higher than that of the wild-type strain during the batch fermentation process. These results show that MuS1-expressing transgenic yeast strain exhibits enhanced alcohol yield as well as tolerance to abiotic stresses, especially metal stress. 相似文献
975.
Jung-Mi Park Myoung-Uoon Jang Jung-Hyun Kang Min-Jeong Kim So-Won Lee Yeong Bok Song Chul-Soo Shin Nam Soo Han Tae-Jip Kim 《Journal of microbiology (Seoul, Korea)》2012,50(6):1041-1046
An endo-arabinanase (BLABNase) gene from Bacillus licheniformis DSM13 was cloned and expressed in Escherichia coli, and the biochemical properties of its encoded enzyme were characterized. The BLABNase gene consists of a single open reading frame of 987 nucleotides that encodes 328 amino acids with a predicted molecular mass of about 36 kDa. BLABNase exhibited the highest activity against debranched α-(1,5)-arabinan in 50 mM sodium acetate buffer (pH 6.0) at 55°C. Enzymatic characterization revealed that BLABNase hydrolyzes debranched or linear arabinans with a much higher activity than branched arabinan from sugar beet. Enzymatic hydrolysis pattern analyses demonstrated BLABNase to be a typical endo-(1,5)-α-s-arabinanase (EC 3.2.1.99) that randomly cleaves the internal α-(1,5)-linked L-arabinofuranosyl residues of a branchless arabinan backbone to release arabinotriose mainly, although a small amount of arabino-oligosaccharide intermediates is also liberated. Our results indicated that BLABNase acts preferentially along with the oligosaccharides longer than arabinopentaose, thus enabling the enzymatic production of various arabino-oligosaccharides. 相似文献
976.
977.
To investigate the contributions of carboxyl-terminal nucleic acid binding domain of HBV core (C) protein for hepatitis B virus (HBV) replication, chimeric HBV C proteins were generated by substituting varying lengths of the carboxyl-terminus of duck hepatitis B virus (DHBV) C protein for the corresponding regions of HBV C protein. All chimeric C proteins formed core particles. A chimeric C protein with 221-262 amino acids of DHBV C protein, in place of 146-185 amino acids of the HBV C protein, supported HBV pregenomic RNA (pgRNA) encapsidation and DNA synthesis: 40% amino acid sequence identity or 45% homology in the nucleic-acid binding domain of HBV C protein was sufficient for pgRNA encapsidation and DNA synthesis, although we predominantly detected spliced DNA. A chimeric C protein with 221-241 and 251-262 amino acids of DHBV C, in place of HBV C 146-166 and 176-185 amino acids, respectively, could rescue full-length DNA synthesis. However, a reciprocal C chimera with 242-250 of DHBV C ((242)RAGSPLPRS(250)) introduced in place of 167-175 of HBV C ((167)RRRSQSPRR(175)) significantly decreased pgRNA encapsidation and DNA synthesis, and full-length DNA was not detected, demonstrating that the arginine-rich (167)RRRSQSPRR(175) domain may be critical for efficient viral replication. Five amino acids differing between viral species (underlined above) were tested for replication rescue; R169 and R175 were found to be important. 相似文献
978.
Md. Suhail Alam Michelle Getz Innocent Safeukui Sue Yi Pamela Tamez Jenny Shin Peter Velázquez Kasturi Haldar 《PloS one》2012,7(10)
Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1−/− mice relative to Npc1+/− at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher’s disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1−/− as well as Balb/c Npc1nmf164 mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1−/− mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1
−/− spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation. 相似文献
979.
JA Ochoa-Alvarez H Krishnan Y Shen NK Acharya M Han DE McNulty H Hasegawa T Hyodo T Senga JG Geng M Kosciuk SS Shin JS Goydos D Temiakov RG Nagele GS Goldberg 《PloS one》2012,7(7):e41845
Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors that have not been identified. We report here that a lectin from the seeds of Maackia amurensis (MASL) with affinity for O-linked carbohydrate chains containing sialic acid targets PDPN to inhibit transformed cell growth and motility at nanomolar concentrations. Interestingly, the biological activity of this lectin survives gastrointestinal proteolysis and enters the cardiovascular system to inhibit melanoma cell growth, migration, and tumorigenesis. These studies demonstrate how lectins may be used to help develop dietary agents that target specific receptors to combat malignant cell growth. 相似文献
980.
S Nishiumi T Kobayashi A Ikeda T Yoshie M Kibi Y Izumi T Okuno N Hayashi S Kawano T Takenawa T Azuma M Yoshida 《PloS one》2012,7(7):e40459