РОЛЬ БЕЛКОВ NOTCH В ПРОЦЕССАХ КАНЦЕРОГЕНЕЗА

Трансмембранные рецепторы семейства Notch, представленные у человека 4 белками (Notch1–4), активируются при непосредственном физическом контакте с клетками, содержащими Notch-лиганды семейств Jagged и Dll. Такое взаимодействие приводит к серии протеолитических расщеплений рецептора, в результате чего его внутриклеточный домен транслоцируется в ядро, и происходит активация транскрипции генов, регулирующих баланс между пролиферацией, клеточной смертью и дифференцировкой. Белки семейства Notch оказывают влияние на внутриклеточные сигнальные пути и межклеточные взаимодействия большинства типов клеток. Notch не только регулирует многие этапы эмбриогенеза, но и участвует в поддержании гомеостаза тканей и органов взрослого организма.
Нарушения активации Notch приводят к различным заболеваниям, в том числе участвуют в канцерогенезе. Наиболее хорошо исследованы нарушения Notch при различных гемобластозах, однако в последние годы выявлено их участие и в инициации и прогрессии солидных опухолей человека. Способность Notch выступать в качестве онкогена или проявлять свойства опухолевого супрессора зависит не только от гистогенетического типа экспрессирующих его клеток, но и от их микроокружения.
В обзоре рассматриваются как канонический сигнальный путь Notch, так и неканонические механизмы его активации, эпигенетическая регуляция, а также современные данные об опухоль-супрессирующих и опухоль-промотирующих эффектах этих белков в злокачественных новообразованиях человека. Отдельное внимание уделено взаимодействию между Notch и другими сигнальными путями, контролирующими процессы эпителиально-мезенхимального перехода, формирования и поддержания фенотипа стволовых клеток и специфических ниш, дифференцировки и ангиогенеза как при нормальном развитии, так и в контексте канцерогенеза. Фармакологическое регулирование активации Notch может быть одним из подходов к терапии многих злокачественных новообразований человека.

Notch, канцерогенез, микроокружение, стволовые клетки опухоли, эпителиально-мезенхимальный переход, ангиогенез, эмбриогенез, внутриклеточная передача сигнала, микроРНК

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