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Christl A. Donnelly - One of the best experts on this subject based on the ideXlab platform.
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assessing the effects of the first 2 years of industry led badger Culling in england on the incidence of bovine tuberculosis in cattle in 2013 2015
Ecology and Evolution, 2017Co-Authors: Lucy A Brunton, Christl A. Donnelly, H Oconnor, Alison Prosser, Stuart Ashfield, Adam Ashton, Paul Upton, Andrew Mitchell, A V Goodchild, Jessica E ParryAbstract:Culling badgers to control the transmission of bovine tuberculosis (TB) between this wildlife reservoir and cattle has been widely debated. Industry-led Culling began in Somerset and Gloucestershire between August and November 2013 to reduce local badger populations. Industry-led Culling is not designed to be a randomized and controlled trial of the impact of Culling on cattle incidence. Nevertheless, it is important to monitor the effects of the Culling and, taking the study limitations into account, perform a cautious evaluation of the impacts. A standardized method for selecting areas matched to Culling areas in factors found to affect cattle TB risk has been developed to evaluate the impact of badger Culling on cattle TB incidence. The association between cattle TB incidence and badger Culling in the first 2 years has been assessed. Descriptive analyses without controlling for confounding showed no association between Culling and TB incidence for Somerset, or for either of the buffer areas for the first 2 years since Culling began. A weak association was observed in Gloucestershire for Year 1 only. Multivariable analysis adjusting for confounding factors showed that reductions in TB incidence were associated with Culling in the first 2 years in both the Somerset and Gloucestershire intervention areas when compared to areas with no Culling (incidence rate ratio (IRR): 0.79, 95% CI: 0.72–0.87, p < .001 and IRR: 0.42, 95% CI: 0.34–0.51, p < .001, respectively). An increase in incidence was associated with Culling in the 2-km buffer surrounding the Somerset intervention area (IRR: 1.38, 95% CI: 1.09–1.75, p = .008), but not in Gloucestershire (IRR: 0.91, 95% CI: 0.77–1.07, p = .243). As only 2 intervention areas with 2 years of data are available for analysis, and the biological cause–effect relationship behind the statistical associations is difficult to determine, it would be unwise to use these findings to develop generalizable inferences about the effectiveness of the policy at present.
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The Duration of the Effects of Repeated Widespread Badger Culling on Cattle Tuberculosis Following the Cessation of Culling
PloS one, 2010Co-Authors: Helen E. Jenkins, Rosie Woodroffe, Christl A. DonnellyAbstract:Background In the British Isles, control of cattle tuberculosis (TB) is hindered by persistent infection of wild badger (Meles meles) populations. A large-scale field trial—the Randomised Badger Culling Trial (RBCT)—previously showed that widespread badger Culling produced modest reductions in cattle TB incidence during Culling, which were offset by elevated TB risks for cattle on adjoining lands. Once Culling was halted, beneficial effects inside Culling areas increased, while detrimental effects on adjoining lands disappeared. However, a full assessment of the utility of badger Culling requires information on the duration of Culling effects. Methodology/Principal Findings We monitored cattle TB incidence in and around RBCT areas after Culling ended. We found that benefits inside culled areas declined over time, and were no longer detectable by three years post-Culling. On adjoining lands, a trend suggesting beneficial effects immediately after the end of Culling was insignificant, and disappeared after 18 months post-Culling. From completion of the first cull to the loss of detectable effects (an average five-year Culling period plus 2.5 years post-Culling), cattle TB incidence was 28.7% lower (95% confidence interval [CI] 20.7 to 35.8% lower) inside ten 100 km2 culled areas than inside ten matched no-Culling areas, and comparable (11.7% higher, 95% CI: 13.0% lower to 43.4% higher, p = 0.39) on lands ≤2 km outside culled and no-Culling areas. The financial costs of Culling an idealized 150 km2 area would exceed the savings achieved through reduced cattle TB, by factors of 2 to 3.5. Conclusions/Significance Our findings show that the reductions in cattle TB incidence achieved by repeated badger Culling were not sustained in the long term after Culling ended and did not offset the financial costs of Culling. These results, combined with evaluation of alternative Culling methods, suggest that badger Culling is unlikely to contribute effectively to the control of cattle TB in Britain.
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The effects of annual widespread badger culls on cattle tuberculosis following the cessation of Culling.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2008Co-Authors: Helen E. Jenkins, Rosie Woodroffe, Christl A. DonnellyAbstract:Summary Background The effective control of human and livestock diseases is challenging where infection persists in wildlife populations. The Randomised Badger Culling Trial (RBCT) demonstrated that, while it was underway, proactive badger ( Meles meles ) Culling reduced bovine tuberculosis (TB) incidence inside culled areas but increased incidence in neighboring areas, suggesting that the costs of such Culling might outweigh the benefits. Objectives and design The objective of this study was to investigate whether Culling impacts persisted more than one year following the cessation of Culling (the ‘post-trial' period). We compared TB incidence in and around RBCT proactive Culling areas with that in and around matched unculled areas. Results : During the post-trial period, cattle TB incidence inside culled areas was reduced, to an extent significantly greater ( p =0.002) than during Culling. In neighboring areas, elevated risks observed during Culling were not observed post-trial ( p =0.038). However, the post-trial effects were comparable to those observed towards the end of the trial (inside RBCT areas: p =0.18 and neighboring areas: p =0.14). Conclusions Although to-date the overall benefits of Culling remain modest, they were greater than was apparent during the Culling period alone. Continued monitoring will demonstrate how long beneficial effects last, indicating the overall capacity of such Culling to reduce cattle TB incidence.
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impacts of widespread badger Culling on cattle tuberculosis concluding analyses from a large scale field trial
International Journal of Infectious Diseases, 2007Co-Authors: Rosie Woodroffe, Christl A. Donnelly, John F Bourne, Gao Wei, Thomas W Johnston, D R Cox, C L CheesemanAbstract:Summary Background Bovine tuberculosis (TB) has re-emerged as a major problem for British cattle farmers. Failure to control the infection has been linked to transmission from European badgers; badger Culling has therefore formed a component of British TB control policy since 1973. Objectives and design To investigate the impact of repeated widespread badger Culling on cattle TB, the Randomised Badger Culling Trial compared TB incidence in cattle herds in and around ten Culling areas (each 100km 2 ) with those in and around ten matched unculled areas. Results Overall, cattle TB incidence was 23.2% lower (95% confidence interval (CI) 12.4–32.7% lower) inside culled areas, but 24.5% (95% CI 0.6% lower–56.0% higher) higher on land ≤2km outside, relative to matched unculled areas. Inside the Culling area boundary the beneficial effect of Culling tended to increase with distance from the boundary ( p =0.085) and to increase on successive annual culls ( p =0.064). In adjoining areas, the detrimental effect tended to diminish on successive annual culls ( p =0.17). On the basis of such linear trends, the estimated net effect per annum for Culling areas similar to those in the trial was detrimental between the first and second culls, but beneficial after the fourth and later culls, for the range of analyses performed. Conclusions Careful consideration is needed to determine in what settings systematic repeated Culling might be reliably predicted to be beneficial, and in these cases whether the benefits of such Culling warrant the costs involved.
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effects of Culling on badger meles meles spatial organization implications for the control of bovine tuberculosis
Journal of Applied Ecology, 2005Co-Authors: Rosie Woodroffe, Christl A. Donnelly, John F Bourne, C L Cheeseman, Richard J Delahay, G Gettinby, J P Mcinerney, Ivan W MorrisonAbstract:1. The incidence of bovine tuberculosis (TB) in British cattle has risen markedly over the last two decades. Failure to control the disease in cattle has been linked to the persistence of a reservoir of infection in European badgers Meles meles, a nationally protected species. Although badger Culling has formed a component of British TB control policy for many years, a recent large-scale randomized field experiment found that TB incidence in cattle was no lower in areas subject to localized badger Culling than in nearby areas where no experimental culls occurred. Indeed, analyses indicated that cattle incidence was higher in culled areas. 2. One hypothesis advanced to explain this pattern is that localized Culling disrupted badgers' territorial behaviour, potentially increasing the rate of contact between cattle and infected badgers. This study evaluated this hypothesis by investigating badger activity and spatial organization in 13 study areas subjected to different levels of Culling. Badger home ranges were mapped by feeding colour-marked baits at badger dens and measuring the geographical area in which colour-marked faeces were retrieved. 3. Badger home ranges were consistently larger in Culling areas. Moreover, in areas not subjected to Culling, home range sizes increased with proximity to the Culling area boundary. Patterns of overlap between home ranges were also influenced by Culling. 4. Synthesis and applications. This study demonstrates that Culling badgers profoundly alters their spatial organization as well as their population density. These changes have the potential to influence contact rates between cattle and badgers, both where culls occur and on adjoining land. These results may help to explain why localized badger Culling appears to have failed to control cattle TB, and should be taken into account in determining what role, if any, badger Culling should play in future control strategies.
Rosie Woodroffe - One of the best experts on this subject based on the ideXlab platform.
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The Duration of the Effects of Repeated Widespread Badger Culling on Cattle Tuberculosis Following the Cessation of Culling
PloS one, 2010Co-Authors: Helen E. Jenkins, Rosie Woodroffe, Christl A. DonnellyAbstract:Background In the British Isles, control of cattle tuberculosis (TB) is hindered by persistent infection of wild badger (Meles meles) populations. A large-scale field trial—the Randomised Badger Culling Trial (RBCT)—previously showed that widespread badger Culling produced modest reductions in cattle TB incidence during Culling, which were offset by elevated TB risks for cattle on adjoining lands. Once Culling was halted, beneficial effects inside Culling areas increased, while detrimental effects on adjoining lands disappeared. However, a full assessment of the utility of badger Culling requires information on the duration of Culling effects. Methodology/Principal Findings We monitored cattle TB incidence in and around RBCT areas after Culling ended. We found that benefits inside culled areas declined over time, and were no longer detectable by three years post-Culling. On adjoining lands, a trend suggesting beneficial effects immediately after the end of Culling was insignificant, and disappeared after 18 months post-Culling. From completion of the first cull to the loss of detectable effects (an average five-year Culling period plus 2.5 years post-Culling), cattle TB incidence was 28.7% lower (95% confidence interval [CI] 20.7 to 35.8% lower) inside ten 100 km2 culled areas than inside ten matched no-Culling areas, and comparable (11.7% higher, 95% CI: 13.0% lower to 43.4% higher, p = 0.39) on lands ≤2 km outside culled and no-Culling areas. The financial costs of Culling an idealized 150 km2 area would exceed the savings achieved through reduced cattle TB, by factors of 2 to 3.5. Conclusions/Significance Our findings show that the reductions in cattle TB incidence achieved by repeated badger Culling were not sustained in the long term after Culling ended and did not offset the financial costs of Culling. These results, combined with evaluation of alternative Culling methods, suggest that badger Culling is unlikely to contribute effectively to the control of cattle TB in Britain.
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The effects of annual widespread badger culls on cattle tuberculosis following the cessation of Culling.
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2008Co-Authors: Helen E. Jenkins, Rosie Woodroffe, Christl A. DonnellyAbstract:Summary Background The effective control of human and livestock diseases is challenging where infection persists in wildlife populations. The Randomised Badger Culling Trial (RBCT) demonstrated that, while it was underway, proactive badger ( Meles meles ) Culling reduced bovine tuberculosis (TB) incidence inside culled areas but increased incidence in neighboring areas, suggesting that the costs of such Culling might outweigh the benefits. Objectives and design The objective of this study was to investigate whether Culling impacts persisted more than one year following the cessation of Culling (the ‘post-trial' period). We compared TB incidence in and around RBCT proactive Culling areas with that in and around matched unculled areas. Results : During the post-trial period, cattle TB incidence inside culled areas was reduced, to an extent significantly greater ( p =0.002) than during Culling. In neighboring areas, elevated risks observed during Culling were not observed post-trial ( p =0.038). However, the post-trial effects were comparable to those observed towards the end of the trial (inside RBCT areas: p =0.18 and neighboring areas: p =0.14). Conclusions Although to-date the overall benefits of Culling remain modest, they were greater than was apparent during the Culling period alone. Continued monitoring will demonstrate how long beneficial effects last, indicating the overall capacity of such Culling to reduce cattle TB incidence.
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impacts of widespread badger Culling on cattle tuberculosis concluding analyses from a large scale field trial
International Journal of Infectious Diseases, 2007Co-Authors: Rosie Woodroffe, Christl A. Donnelly, John F Bourne, Gao Wei, Thomas W Johnston, D R Cox, C L CheesemanAbstract:Summary Background Bovine tuberculosis (TB) has re-emerged as a major problem for British cattle farmers. Failure to control the infection has been linked to transmission from European badgers; badger Culling has therefore formed a component of British TB control policy since 1973. Objectives and design To investigate the impact of repeated widespread badger Culling on cattle TB, the Randomised Badger Culling Trial compared TB incidence in cattle herds in and around ten Culling areas (each 100km 2 ) with those in and around ten matched unculled areas. Results Overall, cattle TB incidence was 23.2% lower (95% confidence interval (CI) 12.4–32.7% lower) inside culled areas, but 24.5% (95% CI 0.6% lower–56.0% higher) higher on land ≤2km outside, relative to matched unculled areas. Inside the Culling area boundary the beneficial effect of Culling tended to increase with distance from the boundary ( p =0.085) and to increase on successive annual culls ( p =0.064). In adjoining areas, the detrimental effect tended to diminish on successive annual culls ( p =0.17). On the basis of such linear trends, the estimated net effect per annum for Culling areas similar to those in the trial was detrimental between the first and second culls, but beneficial after the fourth and later culls, for the range of analyses performed. Conclusions Careful consideration is needed to determine in what settings systematic repeated Culling might be reliably predicted to be beneficial, and in these cases whether the benefits of such Culling warrant the costs involved.
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effects of Culling on badger meles meles spatial organization implications for the control of bovine tuberculosis
Journal of Applied Ecology, 2005Co-Authors: Rosie Woodroffe, Christl A. Donnelly, John F Bourne, C L Cheeseman, Richard J Delahay, G Gettinby, J P Mcinerney, Ivan W MorrisonAbstract:1. The incidence of bovine tuberculosis (TB) in British cattle has risen markedly over the last two decades. Failure to control the disease in cattle has been linked to the persistence of a reservoir of infection in European badgers Meles meles, a nationally protected species. Although badger Culling has formed a component of British TB control policy for many years, a recent large-scale randomized field experiment found that TB incidence in cattle was no lower in areas subject to localized badger Culling than in nearby areas where no experimental culls occurred. Indeed, analyses indicated that cattle incidence was higher in culled areas. 2. One hypothesis advanced to explain this pattern is that localized Culling disrupted badgers' territorial behaviour, potentially increasing the rate of contact between cattle and infected badgers. This study evaluated this hypothesis by investigating badger activity and spatial organization in 13 study areas subjected to different levels of Culling. Badger home ranges were mapped by feeding colour-marked baits at badger dens and measuring the geographical area in which colour-marked faeces were retrieved. 3. Badger home ranges were consistently larger in Culling areas. Moreover, in areas not subjected to Culling, home range sizes increased with proximity to the Culling area boundary. Patterns of overlap between home ranges were also influenced by Culling. 4. Synthesis and applications. This study demonstrates that Culling badgers profoundly alters their spatial organization as well as their population density. These changes have the potential to influence contact rates between cattle and badgers, both where culls occur and on adjoining land. These results may help to explain why localized badger Culling appears to have failed to control cattle TB, and should be taken into account in determining what role, if any, badger Culling should play in future control strategies.
Chengting Chien - One of the best experts on this subject based on the ideXlab platform.
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the proto oncogene int6 is essential for neddylation of cul1 and cul3 in drosophila
PLOS ONE, 2008Co-Authors: Sigal Rencuslazar, Chengting Chien, Yaniv Amir, Junetai Wu, Daniel Chamovitz, Daniel L. SegalAbstract:Int6 is a proto-oncogene implicated in various types of cancer, but the mechanisms underlying its activity are not clear. Int6 encodes a subunit of the eukaryotic translation initiation factor 3, and interacts with two related complexes, the proteasome, whose activity is regulated by Int6 in S. pombe, and the COP9 signalosome. The COP9 signalosome regulates the activity of Cullin-Ring Ubiquitin Ligases via deneddylation of their cullin subunit. We report here the generation and analysis of two Drosophila mutants in Int6. The mutants are lethal demonstrating that Int6 is an essential gene. The mutant larvae accumulate high levels of non-neddylated Cul1, suggesting that Int6 is a positive regulator of cullin neddylation. Overexpression in Int6 in cell culture leads to accumulation of neddylated cullins, further supporting a positive role for Int6 in regulating neddylation. Thus Int6 and the COP9 signalosome play opposing roles in regulation of cullin neddylation.
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neddylation and deneddylation regulate cul1 and cul3 protein accumulation
Nature Cell Biology, 2005Co-Authors: Junetai Wu, Chengting Chien, Yenchen HuAbstract:Cullin family proteins organize ubiquitin ligase (E3) complexes to target numerous cellular proteins for proteasomal degradation. Neddylation, the process that conjugates the ubiquitin-like polypeptide Nedd8 to the conserved lysines of cullins, is essential for in vivo cullin-organized E3 activities1,2. Deneddylation, which removes the Nedd8 moiety, requires the isopeptidase activity of the COP9 signalosome (CSN)3,4. Here we show that in cells deficient for CSN activity, cullin1 (Cul1) and cullin3 (Cul3) proteins are unstable, and that to preserve their normal cellular levels, CSN isopeptidase activity is required. We further show that neddylated Cul1 and Cul3 are unstable — as suggested by the evidence that Nedd8 promotes the instability of both cullins — and that the unneddylatable forms of cullins are stable. The protein stability of Nedd8 is also subject to CSN regulation and this regulation depends on its cullin-conjugating ability, suggesting that Nedd8-conjugated cullins are degraded en bloc. We propose that while Nedd8 promotes cullin activation through neddylation, neddylation also renders cullins unstable. Thus, CSN deneddylation recycles the unstable, neddylated cullins into stable, unneddylated ones, and promotes cullin-organized E3 activity in vivo.
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cul1 and cul3 mediate distinct protein degradation mechanisms to control ci stability in drosophila eye development
Journal of Genetics and Molecular Biology, 2002Co-Authors: Chanyen Ou, Yingjiun Chen, Chengting ChienAbstract:The ubiquitin-like protein, Nedd8, covalently modifies members of the Cullin family. Cullins are the major components of a series of ubiquitin ligases that control the degradation of a broad range of proteins. We found that Nedd8 modifies Cul 1 in Drosophila. In Drosophila Nedd8 and Cul 1 mutants, protein levels of the signal transduction effectors, Cubitus nterruptus (Ci) and Armadillo (Arm), and the cell cycle regulator, Cyclin E (CycE), are highly accumulated, suggesting that the Cul I-based SCF complex requires Nedd8 modification for the degradation processes of Ci, Arm, and CycE in vivo. We further show that two distinct degradation mechanisms odulating Ci stability in the developing eye disc are separated by the morphogenetic furrow (MF) in which retinal differentiation is initiated. In cells anterior to the MF, Ci proteolytic processing promoted by PKA requires the activity of the Nedd8-modified Cull-based SCFslimb complex. In the posterior cells, Ci degradation is controlled by a mechanism that requires the activity of Cul 3, another member of the Cullin family. This posterior Ci degradation mechanism, which partially requires Nedd8 modification, is activated by hedgehog (Hh) signaling and PKA-independent.
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distinct protein degradation mechanisms mediated by cul1 and cul3 controlling ci stability in drosophila eye development
Genes & Development, 2002Co-Authors: Chanyen Ou, Yingjiun Chen, Chengting ChienAbstract:The ubiquitin-like protein, Nedd8, covalently modifies members of the Cullin family. Cullins are the major components of a series of ubiquitin ligases that control the degradation of a broad range of proteins. We found that Nedd8 modifies Cul1 in Drosophila .I nDrosophila Nedd8 and Cul1 mutants, protein levels of the signal transduction effectors, Cubitus interruptus (Ci) and Armadillo (Arm), and the cell cycle regulator, Cyclin E (CycE), are highly accumulated, suggesting that the Cul1-based SCF complex requires Nedd8 modification for the degradation processes of Ci, Arm, and CycE in vivo. We further show that two distinct degradation mechanisms modulating Ci stability in the developing eye disc are separated by the morphogenetic furrow (MF) in which retinal differentiation is initiated. In cells anterior to the MF, Ci proteolytic processing promoted by PKA requires the activity of the Nedd8-modified Cul1-based SCF Slimb complex. In posterior cells, Ci degradation is controlled by a mechanism that requires the activity of Cul3, another member of the Cullin family. This posterior Ci degradation mechanism, which partially requires Nedd8 modification, is activated by Hedgehog (Hh) signaling and is PKA-independent.
Yue Xiong - One of the best experts on this subject based on the ideXlab platform.
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BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase
2016Co-Authors: Manabu Furukawa, Yue XiongAbstract:The concentrations and functions of many eukaryotic proteins are regulated by the ubiquitin pathway, which consists of ubiquitin activation (E1), conjugation (E2), and ligation (E3). Cullins are a family of evolutionarily conserved proteins that assemble by far the largest family of E3 ligase complexes. Cullins, via a conserved C-terminal domain, bind with the RING finger protein Roc1 to recruit the catalytic function of E2. Via a distinct N-terminal domain, individual cullins bind to a protein motif present in multiple proteins to recruit specific substrates. Cullin 3 (Cul3), but not other cullins, binds directly with BTB domains to constitute a potentially large number of BTB-CUL3-ROC1 E3 ubiquitin ligases. Here we report that the human BTB-Kelch protein Keap1, a negative regulator of the antioxidative transcription factor Nrf2, binds to CUL3 and Nrf2 via its BTB and Kelch domains, respectively. The KEAP1-CUL3-ROC1 complex promoted NRF2 ubiquitination in vitro and knocking down Keap1 or CUL3 by short interfering RNA resulted in NRF2 protein accumulation in vivo. We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome. Blocking NRF2 degradation in cells expressing both KEAP1 and NRF2 by either inhibiting the proteasome activity or knocking down Cul3, resulted in NRF2 accumulation in the cytoplasm. These results may reconcile previously observed cytoplasmic seques-tration of NRF2 by KEAP1 and suggest a possible regulatory step between KEAP1-NRF2 binding and NRF
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crl4s the cul4 ring e3 ubiquitin ligases
Trends in Biochemical Sciences, 2009Co-Authors: Sarah Jackson, Yue XiongAbstract:The evolutionarily conserved cullin family proteins can assemble as many as 400 distinct E3 ubiquitin ligase complexes that regulate diverse cellular pathways. CUL4, one of three founding cullins conserved from yeast to humans, uses a large β-propeller protein, DDB1, as a linker to interact with a subset of WD40 proteins that serve as substrate receptors, forming as many as 90 E3 complexes in mammals. Many CRL4 complexes are involved in chromatin regulation and are frequently hijacked by different viruses.
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btb protein keap1 targets antioxidant transcription factor nrf2 for ubiquitination by the cullin 3 roc1 ligase
Molecular and Cellular Biology, 2005Co-Authors: Manabu Furukawa, Yue XiongAbstract:The concentrations and functions of many eukaryotic proteins are regulated by the ubiquitin pathway, which consists of ubiquitin activation (E1), conjugation (E2), and ligation (E3). Cullins are a family of evolutionarily conserved proteins that assemble by far the largest family of E3 ligase complexes. Cullins, via a conserved C-terminal domain, bind with the RING finger protein Roc1 to recruit the catalytic function of E2. Via a distinct N-terminal domain, individual cullins bind to a protein motif present in multiple proteins to recruit specific substrates. Cullin 3 (Cul3), but not other cullins, binds directly with BTB domains to constitute a potentially large number of BTB-CUL3-ROC1 E3 ubiquitin ligases. Here we report that the human BTB-Kelch protein Keap1, a negative regulator of the antioxidative transcription factor Nrf2, binds to CUL3 and Nrf2 via its BTB and Kelch domains, respectively. The KEAP1-CUL3-ROC1 complex promoted NRF2 ubiquitination in vitro and knocking down Keap1 or CUL3 by short interfering RNA resulted in NRF2 protein accumulation in vivo. We suggest that Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome. Blocking NRF2 degradation in cells expressing both KEAP1 and NRF2 by either inhibiting the proteasome activity or knocking down Cul3, resulted in NRF2 accumulation in the cytoplasm. These results may reconcile previously observed cytoplasmic sequestration of NRF2 by KEAP1 and suggest a possible regulatory step between KEAP1-NRF2 binding and NRF2 degradation.
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targeting of protein ubiquitination by btb cullin 3 roc1 ubiquitin ligases
Nature Cell Biology, 2003Co-Authors: Manabu Furukawa, Christoph H Borchers, Yue XiongAbstract:The concentrations and functions of many cellular proteins are regulated by the ubiquitin pathway. Cullin family proteins bind with the RING-finger protein Roc1 to recruit the ubiquitin-conjugating enzyme (E2) to the ubiquitin ligase complex (E3). Cul1 and Cul7, but not other cullins, bind to an adaptor protein, Skp1. Cul1 associates with one of many F-box proteins through Skp1 to assemble various SCF–Roc1 E3 ligases that each selectively ubiquitinate one or more specific substrates. Here, we show that Cul3, but not other cullins, binds directly to multiple BTB domains through a conserved amino-terminal domain. In vitro, Cul3 promoted ubiquitination of Caenorhabditis elegans MEI-1, a katanin-like protein whose degradation requires the function of both Cul3 and BTB protein MEL-26. We suggest that in vivo there exists a potentially large number of BCR3 (BTB–Cul3–Roc1) E3 ubiquitin ligases.
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nedd8 modification of cul1 dissociates p120cand1 an inhibitor of cul1 skp1 binding and scf ligases
Molecular Cell, 2002Co-Authors: Manabu Furukawa, Tomohiro Matsumoto, Yue XiongAbstract:Abstract Cullin proteins assemble a large number of RING E3 ubiquitin ligases and regulate various physiological processes. Covalent modification of cullins by the ubiquitin-like protein NEDD8 activates cullin ligases through an as yet undefined mechanism. We show here that p120 CAND1 selectively binds to unneddylated CUL1 and is dissociated by CUL1 neddylation. CAND1 formed a ternary complex with CUL1 and ROC1. CAND1 dissociated SKP1 from CUL1 and inhibited SCF ligase activity in vitro. Suppression of CAND1 in vivo increased the level of the CUL1-SKP1 complex. We suggest that by restricting SKP1-CUL1 interaction, CAND1 regulated the assembly of productive SCF ubiquitin ligases, allowing a common CUL1-ROC core to be utilized by a large number of SKP1-F box-substrate subcomplexes.
Ivan W Morrison - One of the best experts on this subject based on the ideXlab platform.
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effects of Culling on badger meles meles spatial organization implications for the control of bovine tuberculosis
Journal of Applied Ecology, 2005Co-Authors: Rosie Woodroffe, Christl A. Donnelly, John F Bourne, C L Cheeseman, Richard J Delahay, G Gettinby, J P Mcinerney, Ivan W MorrisonAbstract:1. The incidence of bovine tuberculosis (TB) in British cattle has risen markedly over the last two decades. Failure to control the disease in cattle has been linked to the persistence of a reservoir of infection in European badgers Meles meles, a nationally protected species. Although badger Culling has formed a component of British TB control policy for many years, a recent large-scale randomized field experiment found that TB incidence in cattle was no lower in areas subject to localized badger Culling than in nearby areas where no experimental culls occurred. Indeed, analyses indicated that cattle incidence was higher in culled areas. 2. One hypothesis advanced to explain this pattern is that localized Culling disrupted badgers' territorial behaviour, potentially increasing the rate of contact between cattle and infected badgers. This study evaluated this hypothesis by investigating badger activity and spatial organization in 13 study areas subjected to different levels of Culling. Badger home ranges were mapped by feeding colour-marked baits at badger dens and measuring the geographical area in which colour-marked faeces were retrieved. 3. Badger home ranges were consistently larger in Culling areas. Moreover, in areas not subjected to Culling, home range sizes increased with proximity to the Culling area boundary. Patterns of overlap between home ranges were also influenced by Culling. 4. Synthesis and applications. This study demonstrates that Culling badgers profoundly alters their spatial organization as well as their population density. These changes have the potential to influence contact rates between cattle and badgers, both where culls occur and on adjoining land. These results may help to explain why localized badger Culling appears to have failed to control cattle TB, and should be taken into account in determining what role, if any, badger Culling should play in future control strategies.
