Негативный эндогенный контроль пролиферации клеток в культуре тема диссертации и автореферата по ВАК РФ 03.00.25, доктор биологических наук Сетков, Николай Александрович

• Сетков, Николай Александрович
• доктор биологических наук
• 1997

Оглавление диссертации доктор биологических наук Сетков, Николай Александрович

Введение.

Глава I. Обзор литературы.

1. Пролиферирующие и покоящиеся клетки. Клеточный цикл и периоды покоя (история вопроса).

2. Состояние покоя как особое физиологическое состояние клетки.

3. Уровни регуляции размножения клеток.

4. Косвенные данные о наличии эндогенного механизма регуляции размножения клеток.1.

5. Реактивация ядер покоящихся клеток. Позитивный тип эндогенного контроля размножения клеток.

6. Негативный тип эндогенного контроля размножения клеток.

7. Экзогенная негативная регуляции.

8. Ингибиторы гемопоэтических стволовых клеток.

9. Подавление пролиферации клеток в плотных культурах (ингибиторы, связанные с клеточной поверхностью).

10. Аутокринный механизм подавления пролиферации клеток.

11. Гены и их продукты, экспрессирующиеся селективно в покоящихся клетках.

12. Трансформированные клетки и негативный контроль пролиферации.

13. Дифференцировка клеток и прекращение пролиферации.

14. Потеря стареющими клетками пролиферативного потенциала и негативный контроль пролиферации.

15. Гены и их продукты, обладающие антипролиферативной и антиопухолевой активностью.

16. Протеинкиназы - регуляторы клеточного цикла.

17. О!-циклины, как факторы, лимитирующие скорость прохождения клеткой О ^-периода.

18. Ингибиторы циклин-зависимых киназ (СБ1з).

19. Другие внутриклеточные ингибиторы.

20. Фосфорилирование/дефосфорилирование белков и негативный контроль пролиферации.

Глава II. Материал и методы исследования.

1. Характеристика объекта исследования.

2. Культивирование клеток.

3. Подготовка культуры клеток к опытам. Получение покоящихся и стимулированных клеток.

4. Процедура слияния клеток.

5. Маркирование клеток с помощью изотопов.

6. Приготовление препаратов для радиоавтографического исследования.

7. Идентификация слившихся клеток.

8. Эксперименты с факторами роста.

9. Эксперименты с ингибиторами биосинтеза белка и РНК.

Ю.Эксперименты с окадаевой кислотой.

11.Сбор клеток и измерение включившийся радиоактивности.

12. Норсерн-блот-анализ РНК.

13. Анализ клеточного цикла с помощью метода проточной цитоф луорометрии.

14. Слияние фибробластов и гепатоцитов.

Глава III. Изучение характера эндогенного контроля пролиферации клеток линии NIH ЗТЗ в культуре.

1. Параметры роста культуры клеток линии NIH ЗТЗ в различных условиях культивирования. Пролиферация клеток после переноса в среду с низким содержанием сыворотки.

2. Слияние покоящихся клеток с клетками, стимулированными к пролиферации: ядра стимулированных клеток в гетеродикарионах с покоящимися клетками не вступают в S-период.

3. Синтез ДНК в гетеротрикарионах.

Глава VI. Углубление клеток в состояние покоя.

Глава V. Изучение механизмов, контролирующих пролиферацию клеток, с помощью ингибиторов биосинтеза белка.

Глава VI. Экспрессия генов раннего пролиферативного ответа (протоонкогенов) под влиянием факторов роста и ингибиторов биосинтеза белка.

Глава VII. Синтез ДНК в гетеродикарионах, полученных при слиянии длительно стимулированных клеток с кратковременно стимулированными клетками.

Глава VIII. Синтез ДНК в гетеродикарионах в различных условиях культивирования клеток.

Глава IX. Роль процессов дефосфорилирования в регуляции перехода клеток в состояние пролиферативного покоя и в поддержании этого состояния.

1. Фосфорилирование - дефосфорилирование белков как единый биохимический принцип, лежащий в основе регу-ляторных механизмов.

2. Протеинфосфатаза 2А (РР2А) и ее функции в клетке.

3. Окадаевая кислота и ее биологические эффекты.

4. Влияние окадаевой кислоты на пролиферацию клеток линии NIH ЗТЗ.

Глава X. Роль протеаз и активного протеолиза в регуляции размножения эукариотических клеток.

1. Влияние ингибиторов сериновых протеаз на пролиферацию клеток линии NIH ЗТЗ.

2. Влияние ингибиторов лизосомных цистеиновых протеаз на пролиферацию клеток линии NIH ЗТЗ.

3. Другие лизосомотропные агенты

4. Влияние ингибиторов нелизосомных Са2+-зависимых нейтральных протеаз на пролиферацию клеток линии ШН

Глава XI. Изучение эндогенного контроля в дифференцированных клетках.

Белки - негативные регуляторы - возможные кандидаты на роль эндогенного ингибитора пролиферации.

Введение диссертации (часть автореферата) на тему «Негативный эндогенный контроль пролиферации клеток в культуре»

Значение проблемы клеточного деления настолько ясно, что, говоря о ней, невозможно избежать банальностей."

Д.Мэзия

Реальные клеточные системы - органы и ткани - образованы клетками, различающимися по темпу пролиферации. Многие нормальные ткани содержат значительную по размерам фракцию неразмножающихся клеток. Клетки, не участвующие в общем пролиферативном процессе, были обнаружены и в более простых, чем ткани, клеточных системах - культурах клеток. Поскольку в начале 60-х годов появились данные о том, что клетки, не участвующие в активной пролиферации всей популяци, задерживаются в митотическом цикле до начала Б-периода возникла идея пролиферативного покоя как специфического физиологического состояния клетки (Ьа^Ьа еЬ а1., 1962; Ьа^Ьа, 1963; Ваэе^а, 1968; Ер1£апоуа, ТегзЫкЪ, 1968; 1969). Согласно существующим в настоящее время представлениям, жизненный цикл клетки включает в себя как период активной пролиферации, так и периоды пролиферативного покоя (периоды выхода клеток из митотического цикла).

Переход клеток в состояние покоя означает неограниченное во времени прекращение пролиферативной активности клеток при полном сохранении ими способности к делению.

Важнейшее свойство состояния покоя - его обратимость. Под влиянием соответствующего стимула покоящиеся клетки могут вновь вернуться в митотический цикл. Обратимость состояния покоя позволила Епифановой и Терских (1968) постулировать, что в основе регуляции размножения клеток лежит периодическое чередование в жизненном цикле клетки состояний покоя и активной пролиферации. Тем самым была поставлена задача выяснения механизмов, контролирующих смену этих состояний. С тех пор сравнительно более или менее хорошо были изучены процессы, обеспечивающие прохождение клеткой разных периодов митотического цикла, а также пусковые события, включающие переход покоящейся клетки в цикл, события, протекающие в течение пререпликативного периода. В то же время обратный процесс - переход клетки в состояние покоя, а также процесс поддержания этого состояния в течение неопределенно длительного времени до сих пор остаются с биохимической точки зрения мало понятными событиями в жизненном цикле клетки.

Общая закономерность, выявленная при изучении размножения клеток в культуре, состоит в том, что нормальные диплоидные клетки, а также клетки многих постоянных линий размножаются только при добавлении к питательной среде сыворотки крови или специальных веществ полипептидной природы - факторов роста. В отсутствие в питательной среде таких экзогенных стимуляторов пролиферации клетки переходят в состояние про-лиферативного покоя. Более того, нормальные клетки и клетки ряда минимально трансформированных линий всегда отвечают на субоптимальные условия роста переходом в состояние покоя (Баркан, Никольский, 1985). Согласно ранним представлениям в культурах с субоптимальными условиями роста происходит общее угнетение метаболизма клеток, что естественно сказывается на их пролиферативной активности. Однако подробный сравнительный анализ метаболизма покоящихся и пролиферирующих клеток, проведенный Епифановой (Ер1£апоуа, 1977; 1979; Епифанова и др., 1982), показал, что состояние пролиферативного покоя характеризуется не только снижением общего метаболизма клеток, но и избирательной активацией в них отдельных метаболических процессов. Было сформулировано представление об избирательной активности метаболических процессов как необходимом условии существования покоящихся клеток. Состояние покоя стало рассматриваться не как проявление общего угнетения клеточного метаболизма, а как особое активное физиологическое состояние клетки. Усиление определенных метаболических процессов в покоящихся клетках (обновление долгоживущих макромолекул, активация ферментов катаболизма и т.д.) направлено, главным образом, на выживание клеток и на супрессию клеточного роста с целью предотвращения его несбалансированности в условиях прекращения деления клеток (Епифанова и др., 1982). В последующем накопление данных о регуляции размножения клеток в культуре привело к возникновению представлений о функционировании в них системы внутриклеточного (эндогенного) контроля пролиферации. Переход клеток в состояние покоя стал рассматриваться как результат функционирования эндогенной системы контроля пролиферации.

В настоящее время регуляцию размножения клеток в целом рассматривают на двух основных уровнях ее организации - экзогенном (внешнем по отношению к клетке) и эндогенном (внутриклеточном). В некоторых случаях такое разделение контролирующих пролиферацию механизмов на два уровня регуляции оказывается не совсем правомочным, поскольку клетки могут образовывать и выделять в среду регуляторные вещества, воздействующие на сами клетки продуценты, - аутокринная регуляция. В случае гетерогенных клеточных систем можно говорить о паракринной регуляции. Усложняет общую картину и взаимодействие клеток через межклеточные контакты, изменяющее их пролиферативную активность. При этом сигналы, генерируемые во всех регуляторных звеньях, могут быть как позитивные (стимулирующие пролиферацию), так и негативные (подавляющие пролиферацию).

Основной задачей работы является рассмотрение всех звеньев эндогенной регуляции негативного типа, обеспечивающей возникновение и поддержание состояния пролиферативного покоя.

Вопросы, возникающие при анализе механизмов, контролирующих деление клеток в культуре

В общей проблеме изучения механизмов, контролирующих пролиферацию клеток, один из центральных вопросов заключается в выяснении характера внутриклеточных сигналов, определяющих смену состояний покоя и пролиферации в жизненном цикле клетки.

Теоретически можно допустить следующие варианты эндогенного контроля перехода клеток в состояние покоя:

1. Позитивный тип контроля, при котором в размножающихся клетках имеются факторы, стимулирующие пролиферативные процессы. При этом переход клетки в состояние покоя вызывается прекращением синтеза и истощением эндогенных стимуляторов, или же отсутствием их полного набора.

2. Негативный тип контроля, когда в определенный момент цикла в клетке активируются метаболические процессы, приводящие к появлению эндогенного ингибитора (ингибиторов), препятствующего переходу клетки в очередной этап цикла. При негативном типе эндогенного контроля вступление покоящейся клетки в цикл должно регулироваться снижением концентрации внутриклеточного ингибитора, а не появлением стимулятора пролиферации. Негативный тип контроля может носить: а) специфический характер, когда ингибитор действует на сторого определенный процесс; в этом случае ингибитор может заранее синтезироваться на каком-то этапе клеточного цикла, но действие его проявится только тогда, когда будет протекать чувствительный к нему процесс подготовки клетки к делению; б) неспецифический характер, когда ингибитор, появившись в момент перехода клетки в состояние покоя, блокирует любые процессы, связанные с подготовкой клетки к синтезу ДНК.

Переход клетки в состояние покоя после завершения митоза (Од-состояние), а также блок пролиферации в Ох-, Сг2~ и Даже Б-периодах и, наконец, многопричинность этого состояния (повышение плотности клеток, истощение компонентов среды или отсутствие факторов роста) усложняют исследование проблемы. Здесь прежде всего возникает вопрос об универсальности (или об отсутствии таковой) регуляторных механизмов перехода клеток в состояние покоя при действии различных причин, а также у клеток разного происхождения и различной специализации. Если рассматривать состояние пролиферативного покоя шире, чем просто переход клеток в Ор-период, то возникает также вопрос о механизмах, лежащих в основе прекращения пролиферации при старении клеток, при их дифференцировке, возможной связи этих механизмов между собой. Другими словами это вопрос об идентичности (хотя бы отдельных этапов) механизмов прекращения деления клеток при старении, как необратимом прекращении пролиферации и при обычном выходе клетки из цикла.

Увеличение скорости деградации белков в покоящихся клетках позволяет поставить несколько вопросов. Главный вопрос касается вклада общего протеолиза в регуляцию перехода клеток в состояние покоя и в поддержании этого состояния. Здесь интересна роль лизосом. Обилие и разнообразие протаз ставит вопрос о роли определенных типов протеаз, а также лизосомных и внелизосомных протеаз в отдельности в этом процессе.

Активация в покоящихся клетках фосфатаз также ставит вопрос о связи их с переходом клеток в состояние покоя.

Наконец, последний (но не по значимости) вопрос связан с идентификацией конкретных эффекторных молекул, определяющих смену состояний покоя и активной пролиферации. В работе сделана попытка хотя бы частично ответить на поставленные вопросы.

Характер контроля клеточного размножения можно определить в опытах по слиянию покоящихся и размножающихся клеток. В случае контроля позитивного типа следует ожидать, что ядра покоящихся клеток в ге-теродикарионах будут вовлекаться в пролиферативный процесс. При неспецифическом негативном контроле ингибитор, присутствующий в покоящихся клетках, должен препятствоать переходу ядра пролиферирующей клетки в период синтеза ДНК на любом этапе пререпликативного периода. Наконец, при специфическом негативном контроле подавление вступления ядра пролиферирующей клетки в Б-период будет наблюдаться, если в момент слияния она окажется на этапе подготовки к делению, чувствительном к действию ингибитора.

Имеющийся в литературе экспериментальный материал, полученный ранее в опытах по слиянию клеток, содержит данные, предполагающие как наличие контроля позитивного типа, так и указывающие в пользу существования контроля негативного типа. Причем те и другие данные, сторого говоря, неоднозначны. С одной стороны, в опытах по реактивации покоящихся ядер, подтверждающих идею позитивного контроля, использовали чаще всего линии трансформированных клеток, обладающих высоким пролифера-тивным потенциалом, обусловленным нарушениями нормальной регуляции пролиферации. С другой стороны, данные, указывающие в пользу существования эндогенного контроля негативного типа, были получены только на диплоидных фибробластах человека, обладающих относительно невысокой пролиферативной активностью. Поэтому определенный интерес представляло изучение эндогенного контроля размножения клеток гетероплоидной линии. Кроме того, опыты, результаты которых свидетельствуют в пользу существования контроля негативного типа не позволяют исключить альтернативной гипотезы, согласно которой в гетерокарионах в результате слияния клеток происходит снижение (разбавление), вследствие увеличения объема цитоплазмы, эффективной концентрации стимулятора пролиферации, а не привнесение ингибитора, что и приводит к пассивному подавлению синтеза ДНК. Поэтому главный вопрос, а именно, сущетсвует ли негативная регуляция перехода клеток в состояние покоя и к пролиферации, оставался открытым.

Поскольку не исключено, что клетки разного происхождения могут обладать специфическими особенностями регуляции размножения, в работе проводили слияние покоящихся и стимулированных клеток одной и той же линии. Однако такие, находящиеся в разных состояниях клетки, не имеют морфологических различий. Поэтому главной методической задачей была идентификация продуктов слияния. С этой целью был применен метод двойного изотопного маркирования клеток, позволивший проследить в отдельности за судьбой пролиферирующих и покоящихся ядер в гетерокарионах.

Заключение диссертации по теме «Гистология, цитология, клеточная биология», Сетков, Николай Александрович

ВЫВОДЫ

1. Эксперементальные данные, полученные в работе, однозначно свидетельствуют в пользу существования негативного эндогенного контроля размножения клеток в культуре и позволяют считать, что переход клеток в состояние пролиферативного покоя и его поддержание i

I связаны с выработкой и накоплением ингибитора (ингибиторов) пролиферации, действие которого направлено на подавление реакций подготовки клетки к синтезу ДНК.

2. Главное условие возникновения состояния готовности (компетентности) клеток к переходу в период синтеза ДНК включает в себя как облигатное событие снижение уровня внутриклеточной концентрации эндогенного ингибитора(ов). Поэтому период коммитирования клеток в цикл можно рассматривать как этап пререпликативного периода, когда происходит «выключение» активных механизмов подавления клеточной пролиферации.

3. Приобретение покоящимися клетками компетентности под воздействием факторов роста связано со стимуляцией ими экспрессии генов раннего пролиферативного ответа - c-fos, c-jun, а также с-тус. В противоположность факторам роста ингибиторы биосинтеза белка не только стимулируют экспрессию c-fos, c-jun и c-myc, но и через прямое подавление трансляции приводят к элиминации эндогенного ингибитора(ов) пролиферации. Поэтому внутриклеточный путь стимуляции синтеза ДНК ингибиторами трансляции должен быть короче, чем при воздействии факторов роста.

4. Эндогенный контроль перехода клеток в состояние покоя связан с активностью протеинфосфатаз типа РР2А и, возможно, РР1. 1

Подавление РР2А с помощью окадаевой кислоты стимулирует выход покоящихся клеток в цикл.

I 5. Высокая протеолитическая активность в покоящихся клетках - один из механизмов, способствующих удержанию их в состоянии пролиферативного покоя. Кратковременное подавление или сдвиг катаболических процессов в покоящихся клетках в сторону f анаболических способствует переходу клеток в цикл. Таким образом, кроме специфического лиганд-рецепторного механизма стимуляции

I клеточной пролиферации (факторы роста) существует неспецифический механизм, основанный на кратковременных метаболических сдвигах.

6. В целом полученные результаты подтверждают представление о состоянии пролиферативного покоя, как особом физиологическом состоянии клетки, которое поддерживается с помощью специфических (внутриклеточные ингибиторы) и неспецифических (изменение метаболизма) механизмов.

7. Регуляция размножения гепатоцитов осуществляется по типу позитивного контроля с участием митогенных факторов, образующихся в пролиферирующих гепатоцитах, вне зависимости от способа их стимуляции (гепатоциты регенерирующей после частичной эктомии печени, эмбриональной печени, или печени, стимулированной in vivo токсическими воздействиями). Поэтому различные токсические и другие повреждения паренхимы печени (цирроз) приводят к образованию в ней митогенного фактора(ов), стимулирующего пролиферативную активность фибробластов, что является причиной разрастания соединительно-тканной основы органа.

8. Гепатоциты интактной печени взрослых животных, скорее всего, находятся не в истинном состоянии покоя, или переход их в состояние покоя обусловлен механизмами не связанными с образованием эндогенных ингибиторов, или, наконец, ингибиторы гепатоцитов обладают высокой клеточной специфичностью.

ЗАКЛЮЧЕНИЕ

Регуляция численности клеточных популяций у эукариотов осуществляется главным образом путем регулярной смены состояний активной пролиферации и пролиферативного покоя в результате координированного взаимодействия между внутриклеточными (эндогенными) ингибиторами роста и экстраклеточными (экзогенными) стимуляторами и ингибиторами (факторами роста). Постоянное взаимодействие разных уровней регуляции (экзогенного и эндогенного) приводит к тому, что экзогенные факторы изменяют характер развертывания внутренней программы клетки.

Состояние пролиферативного покоя это - специфическое физиологическое состояние клетки, поддерживаемое избирательно активированными метаболическими процессами и реакциями. Селективная активация определенных метаболических процессов - основной принцип существования покоящихся клеток. Активные процессы в покоящихся клетках направлены, главным образом, на их выживание и подавление пролиферации. Способность прекращать и при необходимости возобновлять клеточную пролиферацию предполагает существование тонкой внутриклеточной регуляторной сети, включающей как позитивные, так и негативные контрольные элементы. Негативный механизм регуляции - общий принцип организации регуля-торных систем, в том числе, контролирующих клеточную пролиферацию.

Во всех эукариотах, от дрожжей до человека, порядок прогрессии клеток в цикле регулируется при участии одних и тех же основных молекул. Активность регуляторных белков и их ассоциация в функциональные комплексы управляются множественными реакциями фосфорилирования дефосфорилирования, происходящими в определенных контрольных пункt тах цикла. Поэтому ключевые роли в регуляции жизненного цикла клетки играют не только цикл-связанные протеинкиназы, но и некоторые протеин-фосфатазы. Эксперименты с окадаевой кислотой демонстрируют определенную функциональную значимость в супрессии клеточного роста протеин-фосфатаз РР2А и РР1.

Негативная регуляция в целом осуществляется при участии ингибиторов пролиферации, которые могут действовать на различных уровнях. Покоящиеся клетки различных типов образуют и освобождают в среду ин-гибиторные молекулы, в основном белки, подавляющие пролиферацию ауто-кринным или паракринным способом. Некоторые из них подобны, если не идентичны, кейлонам. Не ясно могут ли секретируемые ингибиторные белки обеспечивать поддержание состояния покоя.

Данные, полученные в экспериментах по слиянию покоящихся и стимулированных клеток, показывают, что внутриклеточные ингибиторы роста могут быть короткоживущими репрессорными белками. Кратковременная экспозиция покоящихся клеток с ингибиторами трансляции стимулирует, подобно факторам роста, переход клеток в период синтеза ДНК. Возможный механизм, посредствам которого ингибиторы биосинтеза белка стимулируют пролиферацию покоящихся клеток, связан с элиминацией репрессорных белков, удерживающих клетку в состоянии покоя. Эти представления поддерживают исследования биологической роли фактора элонгации 2 (еЕЕ-2)-белка (100 кБа), катализирующего продвижение рибосомы вдоль мРНК и стимулирующего трансляцию (Нуагапоу, Брн^т, 1990; 1993). Этот фактор активен только в нефосфорилированном состоянии. Фосфорилирование еЕЕ-2 вслед за митогенной стимуляцией, через активацию Са2+-/кальмодулин-зависимой еЕЕ-2 киназы, быстро приводит к временной задержке трансляции и остановке биосинтеза белка. В результате этой задержки исчезают некоторые короткоживущие репрессорЫ, что позволяет клетке переходить в цикл.

Таким образом, возобновление пролиферативной активности покоящихся клеток должно включать в себя как облигаторный шаг снижение уровня эндогенного ингибитора(ов).

Во всех этих рассуждения главными являются два вопроса, на которые еще не получены ответы. 1. Какой ключевой процесс должен быть блокирован, чтобы не только прекратилась прогрессия клеток в цикл (им может быть, например, процесс транскрипции любого гена раннего пролифера-тивного ответа (НегккИа е! а1., 1987)), но и клетка перешла в состояние покоя? 2. Какой из известных ингибиторных белков может играть роль эндогенного ингибитора пролиферации?

Скорее всего, клетка будет находиться вне цикла до тех пор пока будут активны: 1) короткоживущие репрессорные белки, подавляющие транскрипцию ключевых генов пререпликативного периода; 2) ингибиторы определенных транскрипционн|,1х факторов; 3) ингибиторы циклин-зависимых киназ; 4) фосфатазы, ревертирующие некоторые ключевые киназные реакции (например, дефосфорилирование рШэ. Однако, переход клетки в истинное состояние пролиферативного покоя, по-видимому, связан с функционированием всех звеньев сложного многофункционального ингибиторного комплекса клетки, включающего в себя протеинфосфатазы, короткоживущие репрессорные белки, рЫЬ и другие ингибиторы транскрипционных факторов, ингибиторы циклин-зависимых киназ и, вероятно, еще не идентифицированные факторы с антипролиферативной активностью. Остается также неясным, формируется ли метаболический статус покоящейся клетки вследствие подавления реакций пререпликативного периода или эти процессы протекают параллельно? По крайней мере участие повышенного протео-лиза белков в покоящихся клетках в деградации Ох-циклинов, как необходимом регуляторном моменте, вполне объяснимо.

В настоящее время могут быть предположительно очерчены три уровня негативного эндогенного контроля перехода клеток из состояния активной пролиферации в состояние покоя и обратно (И<->Р).

1. Быстрые процессы (фосфорилирования/дефосфорилирования), обеспечивающие временный блок клеточного рбста в различных точках цикла.

2. Переход клетки в состояние пролиферативного покоя с продолжительной продукцией ингибиторов, включая короткоживущие репрессорные белки, блокирующие транскрипцию генов раннего пролиферативного ответа.

3. Долговременное поддержание состояния покоя, обеспечиваемое путем изменения метаболизма клетки (сдвиг в сторону катаболических процессов), увеличения степени конденсации хроматина, стабилизации плазматической мембраны и других процессов, не связанных с образованием ингибиторов пролиферации.

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