کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10802420 | 1055694 | 2013 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
MgcRacGAP, a cytoskeleton regulator, inhibits HIF-1 transcriptional activity by blocking its dimerization
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کلمات کلیدی
HIF-2pVHLRACK1receptor of activated protein kinase C 1ARNTCK1bHLHHREsHIF-1αMgcRacGAPEct2HSP90HIF-1MKLP1TACC3AHRSTAT3Per-Arnt-Sim - per-arnt-simROS - ROSaryl hydrocarbon receptor nuclear translocator - اتمسفر هسته ای گیرنده آرویل کربنvon Hippel–Lindau protein - از پروتئین Hippel-Lindaubasic helix–loop–helix - اسلحه پایه حلقه ایPhDs - دکترایhypoxia inducible factor 1 - عامل القایی هیپوکسی 1ODD - فردsignal transducer and activator of transcription 3 - مبدل سیگنال و فعال کننده رونویسی 3PAS - نهHypoxia - هیپوکسیHeat shock protein 90 - پروتئین شوک حرارت 90Mitotic kinesin-like protein 1 - پروتئین مانند کوئینزین متادونی 1prolyl hydroxylases - پرولییل هیدروکسی لیزاCytoskeleton - چارچوب یاخته، سیتواسکلتون، اسکلت سلولیcasein kinase 1 - کازئین کیناز 1Reactive oxygen species - گونههای فعال اکسیژنaryl hydrocarbon receptor - گیرنده آرویل هیدروکربن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Hypoxia inducible factor-1 (HIF-1), a dimeric transcription factor of the bHLH-PAS family, is comprised of HIF-1α, which is inducible by hypoxia and ARNT or HIF-1β, which is constitutively expressed. HIF-1 is involved in cellular homeostasis under hypoxia, in development and in several diseases affected by oxygen availability, particularly cancer. Since its expression is positively correlated with poor outcome prognosis for cancer patients, HIF-1 is a target for pharmaceutical therapy. We have previously shown that male germ cell Rac GTPase activating protein (MgcRacGAP), a regulator of Rho proteins which are principally involved in cytoskeletal organization, binds to HIF-1α and inhibits its transcriptional activity. In this work, we have explored the mechanism of the MgcRacGAP-mediated HIF-1 inactivation. We show that the Myo domain of MgcRacGAP, which is both necessary and sufficient for HIF-1 repression, binds to the PAS-B domain of HIF-1α. Furthermore MgcRacGAP competes with ARNT for binding to the HIF-1α PAS-B domain, as shown by in vitro binding pull down assays. In mammalian cells, ARNT overexpression can overcome the MgcRacGAP-mediated inhibition and MgcRacGAP binding to HIF-1α in vivo inhibits its dimerization with ARNT. We additionally present results indicating that MgcRacGAP binding to HIF-1α is specific, since it does not affect the transcriptional activity of HIF-2, a close evolutionary relative of HIF-1 also involved in hypoxia regulation and cancer. Our results reveal a new mechanism for HIF-1 transcriptional activity regulation, suggest a novel hypoxia-cytoskeleton link and provide new tools for selective HIF-1 inhibition.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1833, Issue 6, June 2013, Pages 1378-1387
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1833, Issue 6, June 2013, Pages 1378-1387
نویسندگان
Aggeliki Lyberopoulou, Ilias Mylonis, George Papachristos, Dimitrios Sagris, Alkmini Kalousi, Christina Befani, Panagiotis Liakos, George Simos, Eleni Georgatsou,