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Senescence surveillance of pre-malignant hepatocytes limits liver cancer development 总被引:1,自引:0,他引:1
Kang TW Yevsa T Woller N Hoenicke L Wuestefeld T Dauch D Hohmeyer A Gereke M Rudalska R Potapova A Iken M Vucur M Weiss S Heikenwalder M Khan S Gil J Bruder D Manns M Schirmacher P Tacke F Ott M Luedde T Longerich T Kubicka S Zender L 《Nature》2011,479(7374):547-551
Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells. 相似文献
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The composition of the gut microbiota is in constant flow under the influence of factors such as the diet, ingested drugs, the intestinal mucosa, the immune system, and the microbiota itself. Natural variations in the gut microbiota can deteriorate to a state of dysbiosis when stress conditions rapidly decrease microbial diversity and promote the expansion of specific bacterial taxa. The mechanisms underlying intestinal dysbiosis often remain unclear given that combinations of natural variations and stress factors mediate cascades of destabilizing events. Oxidative stress, bacteriophages induction and the secretion of bacterial toxins can trigger rapid shifts among intestinal microbial groups thereby yielding dysbiosis. A multitude of diseases including inflammatory bowel diseases but also metabolic disorders such as obesity and diabetes type II are associated with intestinal dysbiosis. The characterization of the changes leading to intestinal dysbiosis and the identification of the microbial taxa contributing to pathological effects are essential prerequisites to better understand the impact of the microbiota on health and disease. 相似文献
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Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs. 总被引:30,自引:0,他引:30
B Margolis P Hu S Katzav W Li J M Oliver A Ullrich A Weiss J Schlessinger 《Nature》1992,356(6364):71-74
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Summary Cytophotometric investigations of lymphocytic populations of 4 sheeps were carried out to determine the diploid standard value for comparative investigations of lymph node cells from sheep with lymphatic leucosis. Inspite of exact and simultaneous preparation there were marked and significant differences in the histograms as well as in the diagrams of absorption level separation. Therefore, the control of several normal cell populations is essential before starting cytophotometric investigations of neoplastic cells.
Diese Arbeit entstand im Rahmen des Sonderforschungsbereiches 47 (Virologie) an der Justus Liebig-Universität Giessen. 相似文献
Diese Arbeit entstand im Rahmen des Sonderforschungsbereiches 47 (Virologie) an der Justus Liebig-Universität Giessen. 相似文献
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Neutrophil elastase targets virulence factors of enterobacteria 总被引:14,自引:0,他引:14
Shigellae cause bacillary dysentery, a bloody form of diarrhoea that affects almost 200 million people and causes nearly 2 million deaths per year. Shigella invades the colonic mucosa, where it initiates an acute inflammation, rich in neutrophils, that initially contributes to tissue damage and eventually resolves the infection. Neutrophils are phagocytic cells that kill microorganisms but it is unclear how neutrophils control pathogenic bacteria expressing virulence factors that manipulate host cells. In contrast to other cells, neutrophils prevent the escape of Shigella from phagocytic vacuoles in which the bacteria are killed. Here we identify human neutrophil elastase (NE) as a key host defence protein: NE degrades Shigella virulence factors at a 1,000-fold lower concentration than that needed to degrade other bacterial proteins. In neutrophils in which NE is inactivated pharmacologically or genetically, Shigella escapes from phagosomes, increasing bacterial survival. NE also preferentially cleaves virulence factors of Salmonella and Yersinia. These findings establish NE as the first neutrophil factor that targets bacterial virulence proteins. 相似文献
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Dax1 is required for testis determination 总被引:11,自引:0,他引:11
The orphan nuclear receptor, Dax1, was originally proposed to act as an 'anti-testis' factor. We find, however, that Nr0b1 (also called Dax1 and Ahch, which encodes Dax1) is in fact required for testis differentiation. 相似文献