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«Антипролиферативное действие карнозина и его производных на опухолевые клетки нейрального происхождения ...»

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ADDIN EN.CITE.DATA [88, 89]. Увеличение уровня белка р16 часто наблюдается в стареющих клетках и сопровождается снижением пролиферативных способностей PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXllc3M8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [90]. Белки р21, р27 и р57, относящиеся к Cip/Kip семейству, связываются с CDK2 и контролируют прогрессию через S фазу PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVycjwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [92-94]. Важную роль в регуляции протеолитических процессов во время клеточного цикла играет Комплекс стимулирующий анафазу (Anaphase promoting complex, АРС), который представляет собой убиквитин-лигазу, фермент катализирующий реакцию присоединения множественных копий белка убиквитина к боковым цепям лизина в молекуле белка-мишени PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdWRha2luPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48

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ADDIN EN.CITE.DATA [95, 96]. Полиубиквитинированние часто является сигналом к деградации белка, которое происходит в 26S протеасоме ADDIN EN.CITE <EndNote><Cite><Author>Hershko</Author><Year>1988</Year><RecNum>423</RecNum><DisplayText>[97]</DisplayText><record><rec-number>423</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">423</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hershko, A.</author></authors></contributors><auth-address>Unit of Biochemistry, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.</auth-address><titles><title>Ubiquitin-mediated protein degradation</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>15237-40</pages><volume>263</volume><number>30</number><edition>1988/10/25</edition><keywords><keyword>Animals</keyword><keyword>Binding Sites</keyword><keyword>Ligases/metabolism</keyword><keyword>Models, Chemical</keyword><keyword>Protein Binding</keyword><keyword>Proteins/ metabolism</keyword><keyword>Ubiquitins/ metabolism</keyword></keywords><dates><year>1988</year><pub-dates><date>Oct 25</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>2844803</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[97]. АРС присутствует в клетке на протяжении всего цикла, однако активность комплекса варьирует. АРС активируется в середине митоза, а ингибирование АРС происходит в конце G1 фазы PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRlcnM8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [98, 99].

Некоторые химические соединения, ионизирующее и УФ излучение, ингибиторы репликации ДНК, а также ошибки при репликации или репарации ДНК приводят к нарушению структуры ДНК и остановке клеточного цикла. Главную роль в этом процессе играют 2 серин/треониновые протеин киназы – АТМ (ataxia telangiectasia mutated) и ATR (ATM-Rad3-related protein). АТМ активируется в ответ на появление двуцепочечных разрывов ДНК, образующиеся под воздействием ионизирующего облучения. ATR активирует под действием УФ-облучения или при нарушениях репликации ДНК. ATM и ATR прикрепляются к сайту повреждения ДНК и фосфорилируют различные белки, в том числе Chk1 и Chk2, которые приводят к остановке клеточного цикла в G1 фазе, препятствуя удвоению ДНК, или в G2 фазе, блокируя вход в митоз PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXN0YW48L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [100-103]. Инициация пролиферации. Сигнальные молекулы, стимулирующие деление клетки, называются митогенами. К наиболее распространенным митогенам относятся факторы роста (ФР; эпидермальный ФР (EGF), ФР фибробластов (FGF), ФР тромбоцитов (PDGF), инсулиноподобный фактор роста (IGF) и др.). Факторы роста связываются со специфическими рецепторами на поверхности клетки, приводя к их активации. Активированные рецепторы индуцируют внутриклеточные сигнальные каскады митоген-активируемых протеинкиназ (mitogen-activated protein kinases, МАРК). Существует 4 вида МАРК: ERK1/2, JNK, p38 и ERK5. Каскад ERK1/2 активируется в ответ на пролиферативные стимулы, например взаимодействие ФР с рецептором на поверхности мембраны. Каскады JNK, p38 и ERK5 активируются в основном при стрессе. ERK1/2 представляют собой консервативные серин/треониновые протеинкиназы, способные фосфорилировать различные белки-мишени в цитопламе, мембранах и ядре, и, таким образом, регулировать большое разнообразие внутриклеточных процессов PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2JpbnNvbjwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+

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ADDIN EN.CITE.DATA [104, 105]. Показано, что активация ERK1/2 необходима для пролиферации клеток. Активированные ERK1/2 киназы принимают участие в синтезе пиримидинов, ремоделировании хроматина, синтезе новых рибосом, активации факторов трансляции и транскрипции, а также в регуляции G1/S и G2/M переходов между фазами клеточного цикла. Ингибирование ERK1/2 приводило к остановке пролиферации и накоплению клеток в одной из фаз клеточного цикла. Финальным шагом ERK1/2 киназ является активация факторов транскрипции (Myc, Elk-1, Sap-1, TIF-IA, и др.), которые индуцируют экспрессию генов, запускающих события клеточного цикла PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFtYmFyZDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+

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ADDIN EN.CITE.DATA [106-109].

G1 фаза. В G1 фазе происходит активный рост новообразованной дочерней клетки, проверяется целостность и равномерность распределения хромосом после митоза. Первым под действием митотического сигнала активируется экспрессия циклинов D (в частности D1), которые образуют комплексы с CDK 4 или CDK 6 ADDIN EN.CITE <EndNote><Cite><Author>Sherr</Author><Year>1993</Year><RecNum>260</RecNum><DisplayText>[110]</DisplayText><record><rec-number>260</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">260</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sherr, C. J.</author></authors></contributors><auth-address>Department of Tumor Cell Biology, St. Jude Children&apos;s Research Hospital, Memphis, Tennessee 38105.</auth-address><titles><title>Mammalian G1 cyclins</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>1059-65</pages><volume>73</volume><number>6</number><edition>1993/06/18</edition><keywords><keyword>Animals</keyword><keyword>Cyclins/ physiology</keyword><keyword>G1 Phase</keyword><keyword>Mammals</keyword></keywords><dates><year>1993</year><pub-dates><date>Jun 18</date></pub-dates></dates><isbn>0092-8674 (Print)&#xD;0092-8674 (Linking)</isbn><accession-num>8513492</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[110]. Главная роль комплекса циклин D1/CDK4/6 заключается в фосфорилировании белка ретинобластомы (retinoblastoma tumor suppressor protein, рRb) и активация фактора транскрипции E2F. В отсутствии митотической стимуляции E2F связан с pRb и поэтому не активен. Фосфорилирование pRb приводит к конформационным изменениям в молекуле pRb и освобождению E2F PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcnRlZ2E8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [111]. E2F связывается со специфической последовательностью ДНК и активирует экспрессию большого количества разнообразных генов необходимых для входа в S фазу, среди них циклины Е и А, ДНК полимераза, белок-ингибитор раннего митоза (early mitotic inhibitor, Emi1) и др. ADDIN EN.CITE <EndNote><Cite><Author>Ohtsubo</Author><Year>1993</Year><RecNum>258</RecNum><DisplayText>[112]</DisplayText><record><rec-number>258</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">258</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ohtsubo, M.</author><author>Roberts, J. M.</author></authors></contributors><auth-address>Department of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98104.</auth-address><titles><title>Cyclin-dependent regulation of G1 in mammalian fibroblasts</title><secondary-title>Science</secondary-title><alt-title>Science (New York, N.Y.)</alt-title></titles><periodical><full-title>Science</full-title><abbr-1>Science (New York, N.Y.)</abbr-1></periodical><alt-periodical><full-title>Science</full-title><abbr-1>Science (New York, N.Y.)</abbr-1></alt-periodical><pages>1908-12</pages><volume>259</volume><number>5103</number><edition>1993/03/26</edition><keywords><keyword>Animals</keyword><keyword>Cell Division/physiology</keyword><keyword>Cell Line</keyword><keyword>Cloning, Molecular</keyword><keyword>Cyclins/genetics/ physiology</keyword><keyword>Fibroblasts/ cytology/metabolism</keyword><keyword>Flow Cytometry</keyword><keyword>G1 Phase/ physiology</keyword><keyword>Gene Expression</keyword><keyword>Genetic Vectors</keyword><keyword>Humans</keyword><keyword>Kanamycin Kinase</keyword><keyword>Male</keyword><keyword>Phosphotransferases/genetics</keyword><keyword>Rats</keyword><keyword>Recombinant Fusion Proteins/metabolism</keyword><keyword>Retroviridae/genetics</keyword><keyword>S Phase/physiology</keyword><keyword>Time Factors</keyword><keyword>Transfection</keyword></keywords><dates><year>1993</year><pub-dates><date>Mar 26</date></pub-dates></dates><isbn>0036-8075 (Print)&#xD;0036-8075 (Linking)</isbn><accession-num>8384376</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[112]. В конце G1 фазы циклин D1 разрушается, что приводит к ингибированию связанных с ним CDK. Разрушение циклина D1 происходит с помощью киназы гликогенсинтетазы (GSK-3), которая фосфорилирует циклин D1 по Thr286, или с помощью Mirk/dyrk киназы, которая фосфорилирует циклин D1 по Thr288. В обоих случаях фосфорилирование влечет за собой деградацию циклина в протеасомах PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWVobDwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [113, 114]. Ингибирование экспрессии циклина D1 препятствует переходу клеток в S фазу. В то время как эктопическая экспрессия циклина D1 ускоряет прогрессию через G1 фазу PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXNncm92ZTwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+

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ADDIN EN.CITE.DATA [115].

Интересно отметить, что для перехода из G1 фазы в S, также необходима активация ERK1/2 с последующей транслокацией протеинкиназы в ядро. Показано, что ERK1/2 индуцирует экспрессию циклина D1, предположительно, через активацию экспрессии генов семейства Fos и Myc. Экспрессия Fos запускается с помощью ERK-активируемого фактора транскрипции Elk. Фосфорилирование Myc по Ser62 с помощью ERK1/2 увеличивает стабильность Myc, который способен напрямую индуцировать экспрессию циклина D1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFtYmFyZDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+

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ADDIN EN.CITE.DATA [106].

В конце G1 фазы находится т.н. точка «Старт» (Start или Restriction point) - контрольная точка, в которой оценивается готовность клетки и благоприятность внешних условий (наличие питательных веществ, факторов роста и др.) к переходу в S фазу и удвоению ДНК. Прошедшая через «Старт» клетка – запрограммирована на репликацию и больше не зависима от внешних стимулов.

К концу G1 фазы возрастает количество циклина Е, который образует комплекс с CDK2. Фосфатаза Cdc25A дефосфорилирует CDK2 по p-Tyr15 и p-Thr14, активируя комплекс циклин Е/CDK2, необходимый для продвижения клетки из G1 в S PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbG9tYmVyZzwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+

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