«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 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 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVycjwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJl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ADDIN EN.CITE.DATA [91]. Ингибирование CKI часто приводит к нарушению контроля пролиферации и опухолевой трансформации PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNO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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 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)
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 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 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 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2JpbnNvbjwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+
PFJlY051bT4zODk8L1JlY051bT48RGlzcGxheVRleHQ+WzEwNCwgMTA1XTwvRGlzcGxheVRleHQ+
PHJlY29yZD48cmVjLW51bWJlcj4zODk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw
cD0iRU4iIGRiLWlkPSJ3MndmeGFmZTZ2YTl6NWVldjJsNTVhYThzeHNhNTk5ZWV2MnMiPjM4OTwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Um9iaW5zb24sIE0uIEouPC9h
dXRob3I+PGF1dGhvcj5Db2JiLCBNLiBILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y
cz48YXV0aC1hZGRyZXNzPlVuaXZlcnNpdHkgb2YgVGV4YXMgU291dGh3ZXN0ZXJuIE1lZGljYWwg
Q2VudGVyLCA1MzIzIEhhcnJ5IEhpbmVzIEJvdWxldmFyZCwgRGFsbGFzLCBUWCA3NTIzNS05MDQs
MSBVU0EuIG1lZ2FuQGhvd2llLnN3bWVkLmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxl
Pk1pdG9nZW4tYWN0aXZhdGVkIHByb3RlaW4ga2luYXNlIHBhdGh3YXlzPC90aXRsZT48c2Vjb25k
YXJ5LXRpdGxlPkN1cnIgT3BpbiBDZWxsIEJpb2w8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxl
PkN1cnJlbnQgb3BpbmlvbiBpbiBjZWxsIGJpb2xvZ3k8L2FsdC10aXRsZT48L3RpdGxlcz48cGVy
aW9kaWNhbD48ZnVsbC10aXRsZT5DdXJyIE9waW4gQ2VsbCBCaW9sPC9mdWxsLXRpdGxlPjxhYmJy
LTE+Q3VycmVudCBvcGluaW9uIGluIGNlbGwgYmlvbG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48
YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q3VyciBPcGluIENlbGwgQmlvbDwvZnVsbC10aXRs
ZT48YWJici0xPkN1cnJlbnQgb3BpbmlvbiBpbiBjZWxsIGJpb2xvZ3k8L2FiYnItMT48L2FsdC1w
ZXJpb2RpY2FsPjxwYWdlcz4xODAtNjwvcGFnZXM+PHZvbHVtZT45PC92b2x1bWU+PG51bWJlcj4y
PC9udW1iZXI+PGVkaXRpb24+MTk5Ny8wNC8wMTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+
QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtLUNhbG1vZHVsaW4tRGVwZW5kZW50IFBy
b3RlaW4gS2luYXNlcy8gbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv
cmQ+PGtleXdvcmQ+TUFQIEtpbmFzZSBLaW5hc2UgMTwva2V5d29yZD48a2V5d29yZD5NQVAgS2lu
YXNlIEtpbmFzZSBLaW5hc2UgMTwva2V5d29yZD48a2V5d29yZD5NYW1tYWxzPC9rZXl3b3JkPjxr
ZXl3b3JkPk1pdG9nZW4tQWN0aXZhdGVkIFByb3RlaW4gS2luYXNlIEtpbmFzZXM8L2tleXdvcmQ+
PGtleXdvcmQ+UHJvdGVpbi1TZXJpbmUtVGhyZW9uaW5lIEtpbmFzZXMvbWV0YWJvbGlzbTwva2V5
d29yZD48a2V5d29yZD5Qcm90ZWluLVR5cm9zaW5lIEtpbmFzZXMvbWV0YWJvbGlzbTwva2V5d29y
ZD48a2V5d29yZD5Qcm90by1PbmNvZ2VuZSBQcm90ZWlucy9tZXRhYm9saXNtPC9rZXl3b3JkPjxr
ZXl3b3JkPlByb3RvLU9uY29nZW5lIFByb3RlaW5zIGMtcmFmPC9rZXl3b3JkPjxrZXl3b3JkPlNp
Z25hbCBUcmFuc2R1Y3Rpb248L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MTk5Nzwv
eWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju
PjA5NTUtMDY3NCAoUHJpbnQpJiN4RDswOTU1LTA2NzQgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np
b24tbnVtPjkwNjkyNTU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxyZW1vdGUtZGF0YWJh
c2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwv
bGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Um9iZXJ0czwvQXV0aG9yPjxZ
ZWFyPjIwMDc8L1llYXI+PFJlY051bT4zODg8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjM4
ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9Incyd2Z4YWZl
NnZhOXo1ZWV2Mmw1NWFhOHN4c2E1OTllZXYycyI+Mzg4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl
Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+
PGF1dGhvcnM+PGF1dGhvcj5Sb2JlcnRzLCBQLiBKLjwvYXV0aG9yPjxhdXRob3I+RGVyLCBDLiBK
LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9u
IG9mIFBoYXJtYWNvdGhlcmFweSBhbmQgRXhwZXJpbWVudGFsIFRoZXJhcGV1dGljcywgTGluZWJl
cmdlciBDb21wcmVoZW5zaXZlIENhbmNlciBDZW50ZXIsIFVuaXZlcnNpdHkgb2YgTm9ydGggQ2Fy
b2xpbmEgYXQgQ2hhcGVsIEhpbGwsIENoYXBlbCBIaWxsLCBOQyAyNzU5OS03Mjk1LCBVU0EuPC9h
dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+VGFyZ2V0aW5nIHRoZSBSYWYtTUVLLUVSSyBtaXRv
Z2VuLWFjdGl2YXRlZCBwcm90ZWluIGtpbmFzZSBjYXNjYWRlIGZvciB0aGUgdHJlYXRtZW50IG9m
IGNhbmNlcjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5PbmNvZ2VuZTwvc2Vjb25kYXJ5LXRpdGxl
PjxhbHQtdGl0bGU+T25jb2dlbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs
bC10aXRsZT5PbmNvZ2VuZTwvZnVsbC10aXRsZT48YWJici0xPk9uY29nZW5lPC9hYmJyLTE+PC9w
ZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5PbmNvZ2VuZTwvZnVsbC10aXRs
ZT48YWJici0xPk9uY29nZW5lPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MzI5MS0z
MTA8L3BhZ2VzPjx2b2x1bWU+MjY8L3ZvbHVtZT48bnVtYmVyPjIyPC9udW1iZXI+PGVkaXRpb24+
MjAwNy8wNS8xNTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48
a2V5d29yZD5EcnVnIERlbGl2ZXJ5IFN5c3RlbXMvIG1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+
RXh0cmFjZWxsdWxhciBTaWduYWwtUmVndWxhdGVkIE1BUCBLaW5hc2VzLyBhbnRhZ29uaXN0cyAm
YW1wOyBpbmhpYml0b3JzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3
b3JkPjxrZXl3b3JkPk1BUCBLaW5hc2UgS2luYXNlIEtpbmFzZXMvIGFudGFnb25pc3RzICZhbXA7
IGluaGliaXRvcnMvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5NQVAgS2luYXNlIFNpZ25h
bGluZyBTeXN0ZW0vIGRydWcgZWZmZWN0cy9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5l
b3BsYXNtcy8gZHJ1ZyB0aGVyYXB5LyBlbnp5bW9sb2d5L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3
b3JkPnJhZiBLaW5hc2VzLyBhbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2dlbmV0aWNzL3Bo
eXNpb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNzwveWVhcj48cHVi
LWRhdGVzPjxkYXRlPk1heSAxNDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5NTAt
OTIzMiAoUHJpbnQpJiN4RDswOTUwLTkyMzIgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVt
PjE3NDk2OTIzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJj
ZS1udW0+MTAuMTAzOC9zai5vbmMuMTIxMDQyMjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJl
bW90ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFu
Z3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==
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 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'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)
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 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)
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 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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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXNncm92ZTwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+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 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 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFtYmFyZDwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+
PFJlY051bT40ODg8L1JlY051bT48RGlzcGxheVRleHQ+WzEwNl08L0Rpc3BsYXlUZXh0PjxyZWNv
cmQ+PHJlYy1udW1iZXI+NDg4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0idzJ3ZnhhZmU2dmE5ejVlZXYybDU1YWE4c3hzYTU5OWVldjJzIj40ODg8L2tleT48
L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5
cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkNoYW1iYXJkLCBKLiBDLjwvYXV0aG9y
PjxhdXRob3I+TGVmbG9jaCwgUi48L2F1dGhvcj48YXV0aG9yPlBvdXlzc2VndXIsIEouPC9hdXRo
b3I+PGF1dGhvcj5MZW5vcm1hbmQsIFAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz
PjxhdXRoLWFkZHJlc3M+SW5zdGl0dXRlIG9mIFNpZ25hbGluZyBEZXZlbG9wbWVudGFsIEJpb2xv
Z3kgYW5kIENhbmNlciwgQ05SUyBVTVIgNjU0MywgVW5pdmVyc2l0ZSBkZSBOaWNlLVNvZmlhIEFu
dGlwb2xpcywgQ2VudHJlIEEuIExhY2Fzc2FnbmUsIDMzIEF2ZW51ZSBkZSBWYWxvbWJyb3NlLCAw
NjE4OSBOaWNlLCBGcmFuY2UuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RVJLIGltcGxp
Y2F0aW9uIGluIGNlbGwgY3ljbGUgcmVndWxhdGlvbjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5C
aW9jaGltIEJpb3BoeXMgQWN0YTwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QmlvY2hpbWlj
YSBldCBiaW9waHlzaWNhIGFjdGE8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs
bC10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvZnVsbC10aXRsZT48YWJici0xPkJpb2NoaW1p
Y2EgZXQgYmlvcGh5c2ljYSBhY3RhPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNh
bD48ZnVsbC10aXRsZT5CaW9jaGltIEJpb3BoeXMgQWN0YTwvZnVsbC10aXRsZT48YWJici0xPkJp
b2NoaW1pY2EgZXQgYmlvcGh5c2ljYSBhY3RhPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFn
ZXM+MTI5OS0zMTA8L3BhZ2VzPjx2b2x1bWU+MTc3Mzwvdm9sdW1lPjxudW1iZXI+ODwvbnVtYmVy
PjxlZGl0aW9uPjIwMDYvMTIvMjY8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFjdGl2ZSBU
cmFuc3BvcnQsIENlbGwgTnVjbGV1czwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3Jk
PjxrZXl3b3JkPkNlbGwgQ3ljbGUvIHBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBQ
cm9saWZlcmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkVuenltZSBBY3RpdmF0aW9uL2RydWcgZWZm
ZWN0czwva2V5d29yZD48a2V5d29yZD5FeHRyYWNlbGx1bGFyIFNpZ25hbC1SZWd1bGF0ZWQgTUFQ
IEtpbmFzZXMvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9ycy9tZXRhYm9saXNtPC9rZXl3b3Jk
PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NQVAgS2luYXNlIFNpZ25hbGluZyBT
eXN0ZW0vZHJ1ZyBlZmZlY3RzLyBwaHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk5lb3BsYXNt
cy9kcnVnIHRoZXJhcHkvZW56eW1vbG9neTwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIEtpbmFz
ZSBJbmhpYml0b3JzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48
eWVhcj4yMDA3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRlPjwvcHViLWRhdGVzPjwv
ZGF0ZXM+PGlzYm4+MDAwNi0zMDAyIChQcmludCkmI3hEOzAwMDYtMzAwMiAoTGlua2luZyk8L2lz
Ym4+PGFjY2Vzc2lvbi1udW0+MTcxODgzNzQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxl
bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouYmJhbWNyLjIwMDYuMTEuMDEwPC9lbGVj
dHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVtb3Rl
LWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0
ZT48L0VuZE5vdGU+
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+
PFJlY051bT4yNzc8L1JlY051bT48RGlzcGxheVRleHQ+WzExNl08L0Rpc3BsYXlUZXh0PjxyZWNv
cmQ+PHJlYy1udW1iZXI+Mjc3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO
IiBkYi1pZD0idzJ3ZnhhZmU2dmE5ejVlZXYybDU1YWE4c3hzYTU5OWVldjJzIj4yNzc8L2tleT48
L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5
cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJsb21iZXJnLCBJLjwvYXV0aG9yPjxh
dXRob3I+SG9mZm1hbm4sIEkuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo
«