PMC:3585731 / 14418-16461 JSON TXT

Annnotations TAB JSON ListView MergeView

testone

pmc-enju-pas

bionlp-st-ge-2016-test-proteins

{"project":"bionlp-st-ge-2016-test-proteins","denotations":[{"id":"T5400","span":{"begin":2031,"end":2035},"obj":"Protein"},{"id":"T5399","span":{"begin":1747,"end":1751},"obj":"Protein"},{"id":"T5398","span":{"begin":1323,"end":1327},"obj":"Protein"},{"id":"T5397","span":{"begin":1179,"end":1183},"obj":"Protein"},{"id":"T5396","span":{"begin":1084,"end":1088},"obj":"Protein"},{"id":"T5395","span":{"begin":1075,"end":1079},"obj":"Protein"},{"id":"T5394","span":{"begin":1035,"end":1040},"obj":"Protein"},{"id":"T5393","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T5392","span":{"begin":740,"end":744},"obj":"Protein"},{"id":"T5391","span":{"begin":612,"end":617},"obj":"Protein"},{"id":"T5390","span":{"begin":451,"end":455},"obj":"Protein"},{"id":"T5389","span":{"begin":280,"end":284},"obj":"Protein"}],"namespaces":[{"prefix":"_base","uri":"http://bionlp.dbcls.jp/ontology/ge.owl#"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

bionlp-st-ge-2016-uniprot

UBERON-AE

{"project":"UBERON-AE","denotations":[{"id":"T5279","span":{"begin":1403,"end":1408},"obj":"http://purl.obolibrary.org/obo/UBERON_0001977"},{"id":"T5278","span":{"begin":398,"end":403},"obj":"http://purl.obolibrary.org/obo/UBERON_0001977"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

GO-BP

GO-MF

{"project":"GO-MF","denotations":[{"id":"T5509","span":{"begin":1328,"end":1343},"obj":"http://purl.obolibrary.org/obo/GO_0016301"},{"id":"T5508","span":{"begin":1902,"end":1905},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T5507","span":{"begin":1274,"end":1277},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T5506","span":{"begin":1031,"end":1034},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T5505","span":{"begin":935,"end":938},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T5504","span":{"begin":604,"end":607},"obj":"http://purl.obolibrary.org/obo/GO_0004705"},{"id":"T5503","span":{"begin":69,"end":72},"obj":"http://purl.obolibrary.org/obo/GO_0004705"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

GO-CC

{"project":"GO-CC","denotations":[{"id":"T5518","span":{"begin":1946,"end":1950},"obj":"http://purl.obolibrary.org/obo/GO_0005623"},{"id":"T5517","span":{"begin":1386,"end":1390},"obj":"http://purl.obolibrary.org/obo/GO_0005623"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

sentences

{"project":"sentences","denotations":[{"id":"T5303","span":{"begin":0,"end":218},"obj":"Sentence"},{"id":"T5309","span":{"begin":1816,"end":2043},"obj":"Sentence"},{"id":"T5308","span":{"begin":1578,"end":1815},"obj":"Sentence"},{"id":"T5307","span":{"begin":1345,"end":1577},"obj":"Sentence"},{"id":"T5306","span":{"begin":706,"end":1344},"obj":"Sentence"},{"id":"T5305","span":{"begin":421,"end":705},"obj":"Sentence"},{"id":"T5304","span":{"begin":219,"end":420},"obj":"Sentence"},{"id":"T94","span":{"begin":0,"end":218},"obj":"Sentence"},{"id":"T95","span":{"begin":219,"end":420},"obj":"Sentence"},{"id":"T96","span":{"begin":421,"end":705},"obj":"Sentence"},{"id":"T97","span":{"begin":706,"end":947},"obj":"Sentence"},{"id":"T98","span":{"begin":948,"end":1344},"obj":"Sentence"},{"id":"T99","span":{"begin":1345,"end":1577},"obj":"Sentence"},{"id":"T100","span":{"begin":1578,"end":1815},"obj":"Sentence"},{"id":"T101","span":{"begin":1816,"end":2043},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

simple1

{"project":"simple1","denotations":[{"id":"T5553","span":{"begin":2031,"end":2035},"obj":"Protein"},{"id":"T5552","span":{"begin":1747,"end":1751},"obj":"Protein"},{"id":"T5551","span":{"begin":1323,"end":1327},"obj":"Protein"},{"id":"T5550","span":{"begin":1179,"end":1183},"obj":"Protein"},{"id":"T5549","span":{"begin":1084,"end":1088},"obj":"Protein"},{"id":"T5548","span":{"begin":1075,"end":1079},"obj":"Protein"},{"id":"T5547","span":{"begin":1035,"end":1040},"obj":"Protein"},{"id":"T5546","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T5545","span":{"begin":740,"end":744},"obj":"Protein"},{"id":"T5544","span":{"begin":612,"end":617},"obj":"Protein"},{"id":"T5543","span":{"begin":451,"end":455},"obj":"Protein"},{"id":"T5542","span":{"begin":280,"end":284},"obj":"Protein"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

BioNLP16_DUT

{"project":"BioNLP16_DUT","denotations":[{"id":"T6428","span":{"begin":1167,"end":1174},"obj":"Negative_regulation"},{"id":"T6427","span":{"begin":1006,"end":1014},"obj":"Positive_regulation"},{"id":"T6426","span":{"begin":1310,"end":1319},"obj":"Positive_regulation"},{"id":"T6425","span":{"begin":1189,"end":1197},"obj":"Positive_regulation"},{"id":"T6424","span":{"begin":1041,"end":1056},"obj":"Phosphorylation"},{"id":"T6423","span":{"begin":535,"end":543},"obj":"Positive_regulation"},{"id":"T6412","span":{"begin":2031,"end":2035},"obj":"Protein"},{"id":"T6410","span":{"begin":1323,"end":1327},"obj":"Protein"},{"id":"T6409","span":{"begin":1179,"end":1183},"obj":"Protein"},{"id":"T6408","span":{"begin":1084,"end":1088},"obj":"Protein"},{"id":"T6407","span":{"begin":1075,"end":1079},"obj":"Protein"},{"id":"T6406","span":{"begin":1035,"end":1040},"obj":"Protein"},{"id":"T6405","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T6404","span":{"begin":740,"end":744},"obj":"Protein"},{"id":"T6403","span":{"begin":612,"end":617},"obj":"Protein"},{"id":"T6402","span":{"begin":451,"end":455},"obj":"Protein"},{"id":"T6401","span":{"begin":280,"end":284},"obj":"Protein"},{"id":"T6411","span":{"begin":1747,"end":1751},"obj":"Protein"}],"relations":[{"id":"R4411","pred":"themeOf","subj":"T6403","obj":"T6423"},{"id":"R4412","pred":"themeOf","subj":"T6406","obj":"T6424"},{"id":"R4413","pred":"themeOf","subj":"T6409","obj":"T6425"},{"id":"R4414","pred":"themeOf","subj":"T6410","obj":"T6426"},{"id":"R4420","pred":"themeOf","subj":"T6424","obj":"T6427"},{"id":"R4421","pred":"themeOf","subj":"T6425","obj":"T6428"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

BioNLP16_Messiy

{"project":"BioNLP16_Messiy","denotations":[{"id":"T6708","span":{"begin":1189,"end":1197},"obj":"Positive_regulation"},{"id":"T6707","span":{"begin":1167,"end":1174},"obj":"Negative_regulation"},{"id":"T6693","span":{"begin":2031,"end":2035},"obj":"Protein"},{"id":"T6692","span":{"begin":1747,"end":1751},"obj":"Protein"},{"id":"T6691","span":{"begin":1323,"end":1327},"obj":"Protein"},{"id":"T6690","span":{"begin":1179,"end":1183},"obj":"Protein"},{"id":"T6689","span":{"begin":1084,"end":1088},"obj":"Protein"},{"id":"T6688","span":{"begin":1075,"end":1079},"obj":"Protein"},{"id":"T6687","span":{"begin":1035,"end":1040},"obj":"Protein"},{"id":"T6686","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T6685","span":{"begin":740,"end":744},"obj":"Protein"},{"id":"T6684","span":{"begin":612,"end":617},"obj":"Protein"},{"id":"T6683","span":{"begin":451,"end":455},"obj":"Protein"},{"id":"T6682","span":{"begin":280,"end":284},"obj":"Protein"}],"relations":[{"id":"R4491","pred":"themeOf","subj":"T6690","obj":"T6708"},{"id":"R4498","pred":"themeOf","subj":"T6708","obj":"T6707"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

DLUT931

{"project":"DLUT931","denotations":[{"id":"T6593","span":{"begin":1167,"end":1174},"obj":"Negative_regulation"},{"id":"T6592","span":{"begin":1189,"end":1197},"obj":"Positive_regulation"},{"id":"T6591","span":{"begin":1057,"end":1066},"obj":"Positive_regulation"},{"id":"T6590","span":{"begin":1041,"end":1056},"obj":"Phosphorylation"},{"id":"T6589","span":{"begin":535,"end":543},"obj":"Positive_regulation"},{"id":"T6588","span":{"begin":439,"end":447},"obj":"Negative_regulation"},{"id":"T6573","span":{"begin":2031,"end":2035},"obj":"Protein"},{"id":"T6572","span":{"begin":1747,"end":1751},"obj":"Protein"},{"id":"T6571","span":{"begin":1323,"end":1327},"obj":"Protein"},{"id":"T6570","span":{"begin":1179,"end":1183},"obj":"Protein"},{"id":"T6564","span":{"begin":612,"end":617},"obj":"Protein"},{"id":"T6563","span":{"begin":451,"end":455},"obj":"Protein"},{"id":"T6562","span":{"begin":280,"end":284},"obj":"Protein"},{"id":"T6569","span":{"begin":1084,"end":1088},"obj":"Protein"},{"id":"T6568","span":{"begin":1075,"end":1079},"obj":"Protein"},{"id":"T6567","span":{"begin":1035,"end":1040},"obj":"Protein"},{"id":"T6566","span":{"begin":763,"end":767},"obj":"Protein"},{"id":"T6565","span":{"begin":740,"end":744},"obj":"Protein"}],"relations":[{"id":"R4436","pred":"themeOf","subj":"T6563","obj":"T6588"},{"id":"R4437","pred":"themeOf","subj":"T6564","obj":"T6589"},{"id":"R4438","pred":"themeOf","subj":"T6567","obj":"T6590"},{"id":"R4439","pred":"themeOf","subj":"T6568","obj":"T6591"},{"id":"R4440","pred":"causeOf","subj":"T6569","obj":"T6591"},{"id":"R4441","pred":"themeOf","subj":"T6570","obj":"T6592"},{"id":"R4452","pred":"themeOf","subj":"T6592","obj":"T6593"}],"text":"Interestingly, we discovered that the phosphorylation of Akt Thr308, JNK and Jun are late events following zVAD.fmk stimulation (Fig. 3B) that coincide with the onset of necroptosis at 6 hr post-stimulation (Fig. S3A). To better understand the contributions of growth factors and RIP1 kinase to necroptotic regulation of Akt, we next analyzed the time course of these phosphorylation changes under serum free conditions. We found that the addition of bFGF alone or in combination with zVAD.fmk led to a substantial rapid and transient increase in both Thr308 and Ser473 phosphorylation of Akt as well as JNK and c-Jun at 15 minutes, reflecting the expected response to growth factor stimulation (Fig. 3C). Significantly, the combination of bFGF/zVAD.fmk, but not bFGF alone, also caused a robust, second, delayed increase in the phosphorylation of Thr308, but not Ser473, of Akt as well as a delayed increase in the phosphorylation of JNK and Jun. Furthermore, Nec-1 had no significant effect on the early increase in both Akt and JNK/c-Jun phosphorylation triggered by both bFGF and bFGF/zVAD, while Nec-1, but not its inactive analog Nec-1i (Fig. S1E), efficiently blocked the bFGF/zVAD increase at 6–9 hr (Fig. 3D), suggesting that only the delayed activation of Akt and JNK is specific for necroptosis and dependent on RIP1 kinase activity. Similarly, IGF/zVAD, which also promoted cell death under serum free conditions, produced a delayed increase in Thr308 phosphorylation on Akt, while IGF alone caused solely an early, transient increase in phosphorylation (Fig. S3C). We confirmed the kinetics of the Akt Thr308 and Ser473 phosphorylation changes using a quantitative ELISA assay, which also showed a robust delayed necroptosis-specific RIP1-dependent increase in Akt Thr308 phosphorylation (Fig. S3D, E). Taken together, these results indicate that the observed delayed increases in Akt and JNK phosphorylation, preceding the onset of cell death, represent specific consequences of necroptotic signaling downstream from RIP1 kinase."}

bionlp-st-ge-2016-test-ihmc

bionlp-st-ge-2016-test-tees

test3

PMC:3585731 / 14418-16461 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:3585731 / 14418-16461 JSON TXT