کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8309024 | 1538502 | 2018 | 35 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A cellular threshold for active ERK1/2 levels determines Raf/MEK/ERK-mediated growth arrest versus death responses
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کلمات کلیدی
4-HT3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromideGAPDHERKRAFFRSPARP4-hydroxytamoxifenERK1/2 - ERK1 / 2MEK1/2 - MEK1 / 2MTT - MTTgrowth arrest - دستگیری رشدMEK - مجاهدین خلقCell death - مرگ سلولی mitogen-activated protein kinase kinase - پروتئین کیناز کیناز فعال Mitogen فعالpoly (ADP-ribose) polymerase - پلی (ADP-ribose) پلیمرازextracellular signal-regulated kinase - کیناز تنظیم شده سیگنال خارج سلولیglyceraldehyde 3-phosphate dehydrogenase - گلیسرولیدید 3-فسفات دهیدروژناز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
In addition to its conventional role for cell proliferation and survival, the Raf/MEK/Extracellular signal-regulated kinase (ERK) pathway can also induce growth arrest and death responses, if aberrantly activated. Here, we determined a molecular basis of ERK1/2 signaling that underlies these growth inhibitory physiological outputs. We found that overexpression of ERK1 or ERK2 switches ÎRaf-1:ER-induced growth arrest responses to caspase-dependent apoptotic death responses in different cell types. These death responses, however, were reverted to growth arrest responses upon titration of cellular phospho-ERK1/2 levels by the MEK1/2 inhibitor AZD6244. These data suggest that a cellular threshold for active ERK1/2 levels exists and affects the cell fate between death and growth arrest. We also found that death-mediating ability of ERK2 is abolished by the catalytic site-disabling Lys52Arg replacement or significantly attenuated by the F-site recruitment site-disabling Tyr261Asn replacement, although unaffected by the mutations that disable the common docking groove or the dimerization interface. Therefore, ERK1/2 mediates death signaling dependently of kinase activity and specific physical interactions. Intriguingly, Tyr261Asn-replaced ERK2 could still mediate growth arrest signaling, further contrasting the molecular basis of ERK1/2-mediated growth arrest and death signaling. These data reveal a mechanism underlying the role of ERK1/2 as a focal point of Raf/MEK/ERK-mediated growth arrest and death signaling.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 42, January 2018, Pages 11-20
Journal: Cellular Signalling - Volume 42, January 2018, Pages 11-20
نویسندگان
Seung-Keun Hong, Pui-Kei Wu, Jong-In Park,