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73.
Mireia Perez Verdaguer Tian Zhang Joao A. Paulo Steven Gygi Simon C. Watkins Hiroaki Sakurai Alexander Sorkin 《The Journal of cell biology》2021,220(7)
Ligand binding triggers clathrin-mediated and, at high ligand concentrations, clathrin-independent endocytosis of EGFR. Clathrin-mediated endocytosis (CME) of EGFR is also induced by stimuli activating p38 MAPK. Mechanisms of both ligand- and p38-induced endocytosis are not fully understood, and how these pathways intermingle when concurrently activated remains unknown. Here we dissect the mechanisms of p38-induced endocytosis using a pH-sensitive model of endogenous EGFR, which is extracellularly tagged with a fluorogen-activating protein, and propose a unifying model of the crosstalk between multiple EGFR endocytosis pathways. We found that a new locus of p38-dependent phosphorylation in EGFR is essential for the receptor dileucine motif interaction with the σ2 subunit of clathrin adaptor AP2 and concomitant receptor internalization. p38-dependent endocytosis of EGFR induced by cytokines was additive to CME induced by picomolar EGF concentrations but constrained to internalizing ligand-free EGFRs due to Grb2 recruitment by ligand-activated EGFRs. Nanomolar EGF concentrations rerouted EGFR from CME to clathrin-independent endocytosis, primarily by diminishing p38-dependent endocytosis. 相似文献
74.
Daisuke Yamazaki Toshiki Itoh Hiroaki Miki Tadaomi Takenawa 《Molecular biology of the cell》2013,24(21):3393-3405
The distinct levels of Rac activity differentially regulate the pattern of intrinsic cell migration. However, it remains unknown how Rac activity is modulated and how the level of Rac activity controls cell migratory behavior. Here we show that Slit-Robo GAP 1 (srGAP1) is a modulator of Rac activity in locomotive cells. srGAP1 possesses a GAP activity specific to Rac1 and is recruited to lamellipodia in a Rac1-dependent manner. srGAP1 limits Rac1 activity and allows concomitant activation of Rac1 and RhoA, which are mutually inhibitory. When both GTPases are activated, the protrusive structures caused by Rac1-dependent actin reorganization are spatially restricted and periodically destabilized, causing ruffling by RhoA-induced actomyosin contractility. Depletion of srGAP1 overactivates Rac1 and inactivates RhoA, resulting in continuous spatiotemporal spreading of lamellipodia and a modal shift of intrinsic cell motility from random to directionally persistent. Thus srGAP1 is a key determinant of lamellipodial dynamics and cell migratory behavior. 相似文献
75.
Hiroaki Horikawa Midori Okada Yuko Nakamura Azusa Sato Noriko Iwamoto 《Free radical research》2013,47(10):1059-1065
The chemical properties of Amadori compounds in the presence of transition metal ions were studied, using the analogs 1-deoxy-1- n -butylamino- d -fructose (DBF) and N f -formyl-fructoselysine (fFL). The following characteristics were revealed: (a) DBF combined easily with Cu 2+ (but no other transition metal ions) to form a DBF-Cu 2+ complex in phosphate buffer, pH 7.4; (b) the complex was unstable, and degraded with the release of Cu + during incubation at 37°C; (c) degradation of the complex was associated with the production of hydroxyl radicals by the Fenton reaction and f -dicarbonyl compounds by non-autoxidative degradation; and (d) properties of DBF were similar to those of fFL. The above properties were additionally observed in glycated poly-Lys (GPL). Our findings indicate a novel mechanism for the generation of hydroxyl radicals and f -dicarbonyl compounds from Amadori adducts in the presence of Cu 2+ . 相似文献
76.
Yoichi Toyama Seiya Yoshida Ryota Saito Hiroaki Kitamura Norimitsu Okui Ryo Miyake Ryusuke Ito Kyonsu Son Teruyuki Usuba Takuya Nojiri Katsuhiko Yanaga 《World journal of surgical oncology》2013,11(1):1-9
Background
Although adjuvant gemcitabine (GEM) chemotherapy for pancreatic cancer is standard, the quality of life (QOL) in those patients is still impaired by the standard regimen of GEM. Therefore, we studied whether mild dose-intensity adjuvant chemotherapy with bi-weekly GEM administration could provide a survival benefit with acceptable QOL to the patients with pancreatic cancer.Methods
After a phase I trial, an adjuvant bi-weekly 1,000 mg/m2 of GEM chemotherapy was performed in 58 patients with pancreatic cancer for at least 12 courses (Group A). In contrast, 36 patients who declined the adjuvant bi-weekly GEM chemotherapy underwent traditional adjuvant 5FU-based chemotherapy (Group B). Careful periodical follow-ups for side effects of GEM and disease recurrence, and assessment of patients’ QOL using the EORTC QOL questionnaire (QLQ-C30) and pancreatic cancer-specific supplemental module (QLQ-PAN26) were performed. Retrospectively, the degree of side effects, patients’ QOL, compliance rate, disease-free survival (DFS), and overall survival (OS) in Group A were compared with those in Group B.Results
No severe side effects (higher than Grade 2 according to the common toxicity criteria of ECOG) were observed, except for patients in Group B, who were switched to the standard GEM chemotherapy. Patients’ QOL was better in Group A than B (fatigue: 48.9 ± 32.1 versus 68.1 ± 36.3, nausea and vomiting: 26.8 ± 20.4 versus 53.7 ± 32.6, diarrhea: 21.0 ± 22.6 versus 53.9 ± 38.5, difficulty gaining weight: 49.5 ± 34.4 versus 67.7 ± 40.5, P < 0.05). Compliance rates in Groups A and B were 93% and 47%. There was a significant difference in the median DFS between both groups (Group A : B =12.5 : 6.6 months, P < 0.001). The median OS of Group A was prolonged markedly compared with Group B (20.2 versus 11.9 months, P < 0.005). For OS between both groups, univariate analysis revealed no statistical difference in 69-year-old or under females, and T1–2 factors, moreover, multivariate analysis indicated three factors, such as bi-weekly adjuvant GEM chemotherapy, T2 or less, and R0.Conclusions
Adjuvant chemotherapy with bi-weekly GEM offered not only the advantage of survival benefits but the excellent compliance with acceptable QOL for postoperative pancreatic cancer patients. 相似文献77.
Hiroaki Ozaki Yoshinori Ogawa Masayuki Mine Hiroaki Sawai 《Nucleosides, nucleotides & nucleic acids》2013,32(5):911-923
Abstract Acridine-modified oligodeoxyribonucleotides (ODNs) at the C5-position of a 2′-deoxyuridine via different lengths of linker arms were synthesized. Reaction of 5-(N-aminoalkyl)carbamoylmethyl-2′-deoxyuridines with 9-phenoxyacridine gave the acridine-modified 2′-deoxyuridines which were incorporated into ODNs. The duplexes containing the acridine-modified strands and their complementary DNA or RNA were thermally more stable than that containing the unmodified strand. Thermal stability of the duplexes of the modified ODNs varied depending on the length of the linker arms. 相似文献
78.
Hiroaki Ozaki Yuichi Sato Sadaji Azuma Hiroaki Sawai 《Nucleosides, nucleotides & nucleic acids》2013,32(3):593-601
Abstract 2′-Deoxy-2′-S-hexyluridine derivative was synthesized from 2,2′-anhydrouridine and 1-hexanethiol and incorporated into an oligodeoxyribonucleotide. The thermal stability of the duplexes formed by the 2′-S-hexyl modified ODN with either the complementary DNA or RNA strand was decreased compared to the unmodified counterparts. 相似文献
79.
Holger Winter Yosuke Maeda Hiroaki Mitsuya Jiri Zemlicka 《Nucleosides, nucleotides & nucleic acids》2013,32(7-9):1341-1345
Abstract Lipophilic phosphodiester L-alaninates of acyclic unsaturated nucleoside analogues 1d, 1e, 2d, 2e, 3d, 3e, 4d and 5d were prepared and their antiretroviral activity was examined in ATH8 cell culture infected with HIV-1. A possible mechanism of action of these analogues is discussed. 相似文献
80.
Diego Ribeiro Migueis Ortega Roberto Hiroaki Nagahama Paulo Cesar Motta Rogério Bertani 《ZooKeys》2013,(352):93-116
The mygalomorph neotropical genus Fufius Simon, 1888 comprises ten species, distributed from Guatemala in Central America to southeastern Brazil, in South America. Most of the species were described from northern South America, in the Amazonian region. Only F. funebris Vellard, 1924 and F. lucasae Guadanucci & Indicatti, 2004 are known from regions more to the south of the continent. Herein we describe three new Brazilian species, Fufius minusculus
sp. n. and F. jalapensis
sp. n. from the state of Tocantins, and F. candango
sp. n. from Distrito Federal. The female of F. lucasae is described for first time and the male and female of F. funebris are redescribed based on specimens collected at the type locality. 相似文献