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81.
Marion C. Hoepflinger Anja Geretschlaeger Aniela Sommer Margit Hoeftberger Christina Hametner Takashi Ueda Ilse Foissner 《Traffic (Copenhagen, Denmark)》2015,16(5):534-554
RAB5 GTPases are important regulators of endosomal membrane traffic. Among them Arabidopsis thaliana ARA7/RABF2b is highly conserved and homologues are present in fungal, animal and plant kingdoms. In land plants ARA7 and its homologues are involved in endocytosis and transport towards the vacuole. Here we report on the isolation of an ARA7 homologue (CaARA7/CaRABF2) in the highly evolved characean green alga Chara australis. It encodes a polypeptide of 202 amino acids with a calculated molecular mass of 22.2 kDa and intrinsic GTPase activity. Immunolabelling of internodal cells with a specific antibody reveals CaARA7 epitopes at multivesicular endosomes (MVEs) and at MVE‐containing wortmannin (WM) compartments. When transiently expressed in epidermal cells of Nicotiana benthamiana leaves, fluorescently tagged CaARA7 localizes to small organelles (putative MVEs) and WM compartments, and partially colocalizes with AtARA7 and CaARA6, a plant specific RABF1 GTPase. Mutations in membrane anchoring and GTP binding sites alter localization of CaARA7 and affect GTPase activity, respectively. This first detailed study of a conventional RAB5 GTPase in green algae demonstrates that CaARA7 is similar to RAB5 GTPases from land plants and other organisms and shows conserved structure and localization. 相似文献
82.
Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes
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Seána Duggan Fabian Essig Kerstin Hünniger Zeinab Mokhtari Laura Bauer Teresa Lehnert Susanne Brandes Antje Häder Ilse D. Jacobsen Ronny Martin Marc Thilo Figge Oliver Kurzai 《Cellular microbiology》2015,17(9):1259-1276
Candida albicans and Candida glabrata account for the majority of candidiasis cases worldwide. Although both species are in the same genus, they differ in key virulence attributes. Within this work, live cell imaging was used to examine the dynamics of neutrophil activation after confrontation with either C. albicans or C. glabrata. Analyses revealed higher phagocytosis rates of C. albicans than C. glabrata that resulted in stronger PMN (polymorphonuclear cells) activation by C. albicans. Furthermore, we observed differences in the secretion of chemokines, indicating chemotactic differences in PMN signalling towards recruitment of further immune cells upon confrontation with Candida spp. Supernatants from co‐incubations of neutrophils with C. glabrata primarily attracted monocytes and increased the phagocytosis of C. glabrata by monocytes. In contrast, PMN activation by C. albicans resulted in recruitment of more neutrophils. Two complex infection models confirmed distinct targeting of immune cell populations by the two Candida spp.: In a human whole blood infection model, C. glabrata was more effectively taken up by monocytes than C. albicans and histopathological analyses of murine model infections confirmed primarily monocytic infiltrates in C. glabrata kidney infection in contrast to PMN‐dominated infiltrates in C. albicans infection. Taken together, our data demonstrate that the human opportunistic fungi C. albicans and C. glabrata are differentially recognized by neutrophils and one outcome of this differential recognition is the preferential uptake of C. glabrata by monocytes. 相似文献
83.
Marciano DK Brakeman PR Lee CZ Spivak N Eastburn DJ Bryant DM Beaudoin GM Hofmann I Mostov KE Reichardt LF 《Development (Cambridge, England)》2011,138(10):2099-2109
Defects in the development or maintenance of tubule diameter correlate with polycystic kidney disease. Here, we report that absence of the cadherin regulator p120 catenin (p120ctn) from the renal mesenchyme prior to tubule formation leads to decreased cadherin levels with abnormal morphologies of early tubule structures and developing glomeruli. In addition, mutant mice develop cystic kidney disease, with markedly increased tubule diameter and cellular proliferation, and detached luminal cells only in proximal tubules. The p120ctn homolog Arvcf is specifically absent from embryonic proximal tubules, consistent with the specificity of the proximal tubular phenotype. p120ctn knockdown in renal epithelial cells in 3D culture results in a similar cystic phenotype with reduced levels of E-cadherin and active RhoA. We find that E-cadherin knockdown, but not RhoA inhibition, phenocopies p120ctn knockdown. Taken together, our data show that p120ctn is required for early tubule and glomerular morphogenesis, as well as control of luminal diameter, probably through regulation of cadherins. 相似文献
84.
85.
Everaerts W Gees M Alpizar YA Farre R Leten C Apetrei A Dewachter I van Leuven F Vennekens R De Ridder D Nilius B Voets T Talavera K 《Current biology : CB》2011,21(4):316-321
Mustard oil (MO) is a plant-derived irritant that has been extensively used in experimental models to induce pain and inflammation. The noxious effects of MO are currently ascribed to specific activation of the cation channel TRPA1 in nociceptive neurons. In contrast to this view, we show here that the capsaicin receptor TRPV1 has a surprisingly large contribution to aversive and pain responses and visceral irritation induced by MO. Furthermore, we found that this can be explained by previously unknown properties of this compound. First, MO has a bimodal effect on TRPA1, producing current inhibition at millimolar concentrations. Second, it directly and stably activates mouse and human recombinant TRPV1, as well as TRPV1 channels in mouse sensory neurons. Finally, physiological temperatures enhance MO-induced TRPV1 stimulation. Our results refute the dogma that TRPA1 is the sole nocisensor for MO and motivate a revision of the putative roles of these channels in models of MO-induced pain and inflammation. We propose that TRPV1 has a generalized role in the detection of irritant botanical defensive traits and in the coevolution of multiple mammalian and plant species. 相似文献
86.
Altomare DA Menges CW Xu J Pei J Zhang L Tadevosyan A Neumann-Domer E Liu Z Carbone M Chudoba I Klein-Szanto AJ Testa JR 《PloS one》2011,6(4):e18828
The CDKN2A/ARF locus encompasses overlapping tumor suppressor genes p16(INK4A) and p14(ARF), which are frequently co-deleted in human malignant mesothelioma (MM). The importance of p16(INK4A) loss in human cancer is well established, but the relative significance of p14(ARF) loss has been debated. The tumor predisposition of mice singly deficient for either Ink4a or Arf, due to targeting of exons 1α or 1β, respectively, supports the idea that both play significant and nonredundant roles in suppressing spontaneous tumors. To further test this notion, we exposed Ink4a(+/-) and Arf(+/-) mice to asbestos, the major cause of MM. Asbestos-treated Ink4a(+/-) and Arf(+/-) mice showed increased incidence and shorter latency of MM relative to wild-type littermates. MMs from Ink4a(+/-) mice exhibited biallelic inactivation of Ink4a, loss of Arf or p53 expression and frequent loss of p15(Ink4b). In contrast, MMs from Arf(+/-) mice exhibited loss of Arf expression, but did not require loss of Ink4a or Ink4b. Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes. The tumor suppressor function of Arf in MM was p53-independent, since MMs with loss of Arf retained functional p53. Collectively, these in vivo data indicate that both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while inactivation of Arf appears to be crucial for MM pathogenesis, the inactivation of both p16(Ink4a) and p19(Arf) cooperate to accelerate asbestos-induced tumorigenesis. 相似文献
87.
Doreen Zegers Sigri Beckers Fenna de Freitas Armand V. Peeters Ilse L. Mertens Stijn L. Verhulst Raoul P. Rooman Jean‐Pierre Timmermans Kristine N. Desager Guy Massa Luc F. van Gaal Wim van Hul 《Obesity (Silver Spring, Md.)》2011,19(1):152-159
The melanocortin‐3 receptor (MC3R), a G‐protein‐coupled receptor expressed in the hypothalamus, is a key component of the leptin‐melanocortin pathway that regulates energy homeostasis. It is suggested that an MC3R defect leads to an increased feed efficiency, by which nutrients are partitioned preferentially into fat. In this study, we hypothesized that early‐onset obesity could be induced by mutations in MC3R. To investigate this hypothesis, we screened the entire coding region of the MC3R gene for mutations in obese subjects. A total of 404 overweight and obese children and adolescents, 86 severely obese adults (BMI ≥40 kg/m2), and 150 normal‐weight control adults were included. Besides three synonymous coding variations in the MC3R gene (S69S, L95L, I226I), we were able to identify three novel heterozygous, nonsynonymous, coding mutations (N128S, V211I, L299V) in three unrelated obese children. None of these mutations were found in any of the control subjects. Functional studies assessing localization and signaling properties of the mutant receptors provided proof for impaired function of the L299V mutated receptor, whereas no conclusive evidence for functional impairment of the N128S and V211I mutated receptors could be established. First, these results provide supporting evidence for a role of the MC3R gene in the pathogenesis of obesity in a small subset of patients. Second, they show that caution is called for the interpretation of newly discovered mutations in MC3R. 相似文献
88.
Eveline Dirinck Philippe G. Jorens Adrian Covaci Tinne Geens Laurence Roosens Hugo Neels Ilse Mertens Luc van Gaal 《Obesity (Silver Spring, Md.)》2011,19(4):709-714
Persistent organic pollutants (POPs) are endocrine‐disrupting chemicals associated with the development of the metabolic syndrome and type 2 diabetes. In humans, little is known about their role in the potential origin of obesity. This study aims to assess the associations between serum levels of POPs and the prevalence of obesity in a cohort of obese and lean adult men and women. POP serum samples were investigated cross‐sectionally in 98 obese and 47 lean participants, aged ≥18 years. Serum samples were analyzed for the presence of polychlorinated biphenyl (PCB) congeners 153, 138, 180, and 170 and for the organochlorine pesticides, dichloro‐diphenyl‐dichloroethylene (pp‐DDE), and β‐hexachlorocyclohexane (βHCH). We established a significant negative correlation between BMI, waist, fat mass percentage, total and subcutaneous abdominal adipose tissue, and serum levels of PCB 153, 180, 170, and the sumPCBs. For βHCH, we demonstrated a positive correlation with BMI, waist, fat mass percentage, and total and subcutaneous abdominal adipose tissue. PCBs 180, 170, and the sum of PCBs correlated significantly negative with homeostasis model assessment for insulin resistance (HOMAIR). βHCH correlated significantly positively with HOMAIR. A strong correlation was established between all POP serum levels and age. We established a positive relationship between high serum levels of βHCH and BMI and HOMAIR, whereas serum PCB levels were inversely correlated with BMI and HOMAIR. Combined, these results suggest that the diabetogenic effect of low‐dose exposure to POPs might be more complicated than a simple obesogenic effect. 相似文献
89.
Colvin EK Susanto JM Kench JG Ong VN Mawson A Pinese M Chang DK Rooman I O'Toole SA Segara D Musgrove EA Sutherland RL Apte MV Scarlett CJ Biankin AV 《PloS one》2011,6(12):e29075
Background
Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer (PC). These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials in the treatment of several cancer types. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in PC.Methodology/Principal Findings
We investigated the role of retinoid signaling in vitro and in vivo in normal pancreas, pancreatic injury, regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during injury and regeneration. Both chemically induced and genetically engineered mouse models of PC exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1), a key regulator of retinoid signaling known to play a role in breast cancer development, as a potential therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human PC, and was evident in the very earliest precursor lesions (PanIN-1A). However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter PC sensitivity to retinoid based therapies.Conclusions/Significance
In conclusion, retinoid signalling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1. 相似文献90.
Ilse L. Ackerman Reginaldo Constantino Hugh G. Gauch Jr . Johannes Lehmann Susan J. Riha Erick C. M. Fernandes 《Biotropica》2009,41(2):226-233
Termites play important roles in organic matter decomposition, nutrient cycling, and soil structure in tropical rain forests. When forests are replaced by agriculture, termite species richness, abundance, and function often decline. We compared the termite assemblage of a primary forest site with that of a low plant diversity, palm-based agroforest (five plant species) and a high plant diversity, home-garden agroforest (10 plant species) using a rapid biodiversity assessment protocol. In comparing the primary forest termite species composition to previously published studies, we found soil feeders and the Apicotermitinae to be more dominant than previously reported in Amazonia. Thirty percent of the species belonged to the Apicotermitinae, and an unusually high percentage (57%) of species were soil feeders. Unexpectedly, the palm-based agroforest, despite its lower plant diversity, was closer to primary forest in termite species composition, rate of species accumulation, and proportions of species in taxonomic and functional classes than was the home-garden agroforest. This suggests that particular plant attributes may better determine the termite assemblage than plant diversity alone in these agroecosystems. Unlike other agroecosystems reported in the literature, Apicotermitinae and soil feeders were proportionally more abundant in these agroforests than in primary forest. The ability of agroforests to support populations of soil feeders has a potentially positive effect on soil fertility in these agroecosystems; insomuch as feeding guild is a proxy for function, these closed-canopy agroforests may be able to sustain the same termite-mediated functions as primary forest. 相似文献