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Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2
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نویسنده
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scortegagna m. ,kim h. ,li j.-l. ,yao h. ,brill l.m. ,han j. ,lau e. ,bowtell d. ,haddad g. ,kaufman r.j. ,ronai z.a.
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منبع
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plos genetics - 2014 - دوره : 10 - شماره : 5
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چکیده
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The endoplasmic reticulum (er) responds to changes in intracellular homeostasis through activation of the unfolded protein response (upr). yet,it is not known how upr-signaling coordinates adaptation versus cell death. previous studies suggested that signaling through perk/atf4 is required for cell death. we show that high levels of er stress (i.e.,ischemia-like conditions) induce transcription of the ubiquitin ligases siah1/2 through the upr transducers perk/atf4 and ire1/sxbp1. in turn,siah1/2 attenuates proline hydroxylation of atf4,resulting in its stabilization,thereby augmenting er stress output. conversely,atf4 activation is reduced upon siah1/2 kd in cultured cells,which attenuates er stress-induced cell death. notably,siah1a+/-::siah2-/- mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death,compared with the wild type (wt) mice. in all,siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe er stress conditions. © 2014 scortegagna et al.
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آدرس
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tumor initiation and maintenance program,cancer center,sanford-burnham medical research institute,la jolla,ca, United States, tumor initiation and maintenance program,cancer center,sanford-burnham medical research institute,la jolla,ca, United States, proteomics facility,sanford-burnham medical research institute,la jolla,ca, United States, department of pediatrics,university of california,san diego,la jolla,ca, United States, proteomics facility,sanford-burnham medical research institute,la jolla,ca, United States, degenerative diseases program,sanford-burnham medical research institute,la jolla,ca, United States, tumor initiation and maintenance program,cancer center,sanford-burnham medical research institute,la jolla,ca, United States, department of biochemistry and molecular biology,the university of melbourne,parkville,vic,australia,department of pathology,the university of melbourne,parkville,vic,australia,sir peter maccallum department of oncology,the university of melbourne,parkville,vic,australia,cancer genomics and genetics,peter maccallum cancer centre,east melbourne,vic, Australia, department of pediatrics,university of california,san diego,la jolla,ca, United States, degenerative diseases program,sanford-burnham medical research institute,la jolla,ca, United States, tumor initiation and maintenance program,cancer center,sanford-burnham medical research institute,la jolla,ca, United States
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Authors
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