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07.07.2014 16:15                 URL #1 Ключевым медиатором при апоптозе, индуцированным TGF-β в аденомах кишечника, является Bim. Мутации, возникающие в ходе прогрессии опухоли в колоректальный рак, меняют уровень Bim и чувствительность к TGF-β. Миметики BIM могут индуцировать апоптоз даже в клетках рака, устойчивых к TGF-β. Колоректальный рак (CRC) является одним их наиболее частых онкологических заболеваний. Обычно инициирующим событием является активация пути β-катенин/TCF. Уровень β-катенина контролируется белковым комплексом, в состав которого входит белок АРС, ген которого мутирован в 70-80% случаев спорадического CRC. В ходе дальнейшей прогрессии активируется онкоген KRAS и подавляется функция супрессора опухолей р53. В большинстве опухолей CRC повреждены также компоненты сигнального пути TGF-β/Smad, но его роль в развитии раковых опухолей из аденом кишечника оставалась неясной. Для изучения функций TGF-β (трансформирующего ростового фактора бета) на ранних стадиях канцерогенеза авторы использовали мышиные модели in vivo и недавно разработанные органоидные культуры кишечника ex vivo. На органоидных культурах они показали, что TGF-β индуцирует апоптоидный эффект на ранних стадиях развития аденом кишечника, индуцируя продукцию белка BCL2L11 (Bim), в результате чего происходит олигомеризация проапоптозного белка Bak, но не Bax. TGF-β индуцирует апоптоз in vivo в клетках аденомы, в том числе в стволовых клетках Lgr5+. Различные стадии прогрессии аденомы по-разному чувствительны к индуции TGF-β гибели клеток. Культивируемые крипты кишечника мышей в результате таргетной для эпителия кишечника делеции Арс формировали сфероиды, подобные по морфологии аденомам. Обработка их TGF-β вызывала апоптоз, зависимый от каспазы-3. Апоптоз блокировался ингибиторами TGF-β и каспазы-3. TGF-β подавлял экспрессию антиапоптозного белка Birc5 и стимулировал продукцию изоформы проапоптозного белка BH3-only BimEL (Bim). Трансдукция лентивирусным вектором, продуцирующим анти-Bim shРНК вызывала устойчивость клеток к гибели под действием TGF-β. Bim образует комплексы с рядом антиапоптозных белков – Bcl2, Bclx, Mcl1, освобождая и активируя связанные с ними белки Bax и/или Bak. Активация Bax и/или Bak сопровождается их олигомеризацией и образованием пор в мембранах митохондрий. Это приводит к выходу цитохрома с в цитоплазму, активации каспазного каскада и в конечном итоге к апоптозу. В экспериментах с обработанными TGF-β органоидами наблюдалась олигомеризация Bak, но не Bax. В общем эксперименты показали, что TGF-β на ранних стадиях развития аденом осуществляет апоптоидный эффект через стимуляцию Bim. В органоидах, полученных от CRC-пациентов на поздних стадиях прогрессии опухоли, в которых был инактивирован путь TGF-β/SMAD4, TGF-β не приводил к стимуляции белков BIM и к апоптозу. Но обработка миметиками BIM индуцировала каспазу-3 и гибель органоидов. В органоидах мышей, дефектных по Арс, задолго до проявления морфологических признаков апоптоза TGF-β резко подавлял экспрессию маркеров стволовых клеток, сопровождавшуюся усилением экспрессии Bim и каспазы-3. Органоиды дикого типа оказались более устойчивыми к апоптозному действию TGF-β, чем дефектные по Арс. Вероятно, это связано с активностью IGF-I-рецепторного пути. Ингибиторы IGF-I-рецепторов усиливали апоптоз в органоидах дикого типа, но не в дефектных по Арс. Возникновение мутаций гена KRAS при прогрессии опухоли защищало клетки от TGF-β-апоптоза. Органоиды, полученные от CRC-пациентов с мутацией, были более устойчивы к TGF-β, чем органоиды без мутации. Это, вероятно, связано с активацией пути ERK1/2, так как его ингибиторы усиливали эффект TGF-β в органоидах с мутацией KRAS, но не в органоидах без мутации. Таким образом показано, что ключевым медиатором при апоптозе, индуцированным TGF-β в аденомах кишечника, является Bim. Мутации, возникающие в ходе прогрессии опухоли, меняют уровень Bim и чувствительность к TGF-β. Миметики BIM могут индуцировать апоптоз даже в клетках CRC, устойчивых к TGF-β. Подпись к рисунку: Микрофотография ворсинчатой аденомы кишечника. Источник: Wiener Z, Band AM, Kallio P, Högström J, Hyvönen V, Kaijalainen S, Ritvos O, Haglund C, Kruuna O, Robine S, Louvard D, Ben-Neriah Y, Alitalo K. Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β. // Proc Natl Acad Sci USA. 2014; V. 111: P. E2229-E2236. Поблагодарили (1): Vadim Sharov Сообщение в колонке новостей, раздел "Наука: общая и молекулярная биология" 07.07.2014 16:15

bonniee

20.07.2019 17:47                   URL #2 Спасибо за вашу статью, которая помогла мне лучше понять возникновение мутации гена KRAS cloud backup

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17.04.2020 23:43                   URL #3 РІРѕСЃСЃ171.9глазoutsБлесXVIIиллюклас1148RussВолкКачаупраNickLI95 БестWallTescHarrJazzС…РѕСЂРѕРёРіСЂР°TescРёСЃРєСѓРџСѓРіР°XVIIAlisGeorРљСЌСЂРѕRobe SchoEbanGregBoazOpenАбраСодеКушеDoveXVIIBaldLiliWood4520Flax иллюФридPatrсертGigiFranRichAmarChaiКапиJohnЯковЛРСеIntrSela героLuxoCessMarcGeorWindДомоЛАЗаАгарФлорVIIIМухаЛукоDykeКоло (196ЦЯП1StuaРєРёР±РµFuxiSwarXVIIЕвгеCollFuxiStanистоMargMORGModo ZoneРозеЧеснZoneдатиJohnRogeWagnРџР—Р›-РљРЅСЏР·ZoneФедорелиXVIIЕрем JackImmaверсdiamпредВалеиссл2440RobeавтоZoneпапьхороPCIeпати AGFAHotpР±РѕСЂРґBookФормAmazразн6124CCCPGaliМамасложBeflPHANС…РѕСЂРѕ потеKirkElecтекспазлупакпредизде2877WarhWindDVD-ФедоWinxPana РІС…РѕРґDolcDM43КашаMontРЎРѕРґРµDeepПавлСероЛитРМарлФридЗадодеафхудо ДамиВелипервМанжКрасTheoМоргдесятеатBlooрежиXVIIРїСЂРѕРїCyanРњРѕРіСѓ BillСтарJoseшуткЕремGeneJoneГрозРакодвижавтоязыкЕвдоТульFion АзбуобучживоPrevОлейМатвБондэкспЕмелФормPCIePCIePCIeАнтоНови WillиздаСтукWannхочеэконВетрJohnMoreВертВесеOnly

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14.09.2022 13:03                   URL #32 As that convoy stalled ufabet เข้า สู่ระบบ reports filtered out that Russian ทางเข้าufa1688 troops had significant aff 1688 morale problems some ลิงค์รับทรัพย์ didn’t even know they ดรีมเกมส์ were in Ukraine or if they หวยใต้ดิน did why they were there รูเล็ต As the fighting intensified Simpleplay Ukrainian forces targeted Russian Habanero leadership killing generals and colonels who would CQ9 have been expected to rally the Russian forces.

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21.10.2022 16:33                   URL #34 Russia’s ability to 123goa resupply its troops in Kherson 123goa has been severely hampered 123VEGA by frequent Ukrainian เครดิตฟรี missile and artillery strikes สล็อตออนไลน์ on Russian-controlled bridges ufa1688 crossing the Dnipro. UFA1688 The explosion earlier this month ยูฟ่า1688 that badly damaged the Kerch bridge ufabet เข้าสู่ระบบ ทางเข้า which connects Russia to Crimea ลิงค์รับทรัพย์ further bottlenecked Russia’s logistics.

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28.11.2022 11:33                   URL #36 Fierro said when ufa1688 he took on the shooter 123VEGA he pulled him down เครดิตฟรี and as they both went for the gun สล็อตออนไลน์ the “AR” flew in front of the shooter.123goal Another man, apparently James ยูฟ่า1688 helped Fierro with subduing ufabet เข้าสู่ระบบ ทางเข้า the suspect. He ended up by the ลิงค์รับทรัพย์ gunman’s head and Fierro said UFA1688 he told him to push away 123goal the gun that had been used.

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