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51.
All animals and plants dynamically attach and remove O-linked beta-N-acetylglucosamine (O-GlcNAc) at serine and threonine residues on myriad nuclear and cytoplasmic proteins. O-GlcNAc cycling, which is tightly regulated by the concerted actions of two highly conserved enzymes, serves as a nutrient and stress sensor. On some proteins, O-GlcNAc competes directly with phosphate for serine/threonine residues. Glycosylation with O-GlcNAc modulates signalling, and influences protein expression, degradation and trafficking. Emerging data indicate that O-GlcNAc glycosylation has a role in the aetiology of diabetes and neurodegeneration. 相似文献
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Gallo EM Winslow MM Canté-Barrett K Radermacher AN Ho L McGinnis L Iritani B Neilson JR Crabtree GR 《Nature》2007,450(7170):731-735
At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the alphabeta T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide-MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates. 相似文献
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TJ Pugh SD Weeraratne TC Archer DA Pomeranz Krummel D Auclair J Bochicchio MO Carneiro SL Carter K Cibulskis RL Erlich H Greulich MS Lawrence NJ Lennon A McKenna J Meldrim AH Ramos MG Ross C Russ E Shefler A Sivachenko B Sogoloff P Stojanov P Tamayo JP Mesirov V Amani N Teider S Sengupta JP Francois PA Northcott MD Taylor F Yu GR Crabtree AG Kautzman SB Gabriel G Getz N Jäger DT Jones P Lichter SM Pfister TM Roberts M Meyerson SL Pomeroy YJ Cho 《Nature》2012,488(7409):106-110
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MJ Claesson IB Jeffery S Conde SE Power EM O'Connor S Cusack HM Harris M Coakley B Lakshminarayanan O O'Sullivan GF Fitzgerald J Deane M O'Connor N Harnedy K O'Connor D O'Mahony D van Sinderen M Wallace L Brennan C Stanton JR Marchesi AP Fitzgerald F Shanahan C Hill RP Ross PW O'Toole 《Nature》2012,488(7410):178-184
Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing. 相似文献
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Tavazoie SF Alarcón C Oskarsson T Padua D Wang Q Bos PD Gerald WL Massagué J 《Nature》2008,451(7175):147-152