Взаимосвязь гена TP53 с ретроэлементами в канцерогенезе

В настоящем обзоре представлены сведения о роли гена TP53 в канцерогенезе рака предстательной железы, почки и мочевого пузыря за счет негативной регуляции ретротранспозонов. Белок р53 является транскрипционным фактором, управляющим экспрессией различных белок-кодирующих генов. Промоторные области эндогенных ретровирусов содержат практически идеальные сайты связывания с белком р53, который подавляет их трансляцию, а также вызывает сайленсинг ретроэлементов LINE1. Сам ген TP53 содержит в своем составе ретротранспозоны, которые способствуют мутациям вследствие рекомбинаций. Герминальные мутации гена ТР53 при синдроме Ли– Фраумени вызывают дефицит белка р53, что ведет к активации ретроэлементов, которые, в свою очередь, вызывают потерю гетерозиготности 2-го аллеля ТР53. Возникает порочный круг, стимулирующий геномную нестабильность и канцерогенез. Данный механизм возможен для спорадических злокачественных новообразований мочеполовой системы, при которых наиболее часто выявляют мутации TP53, действующие как драйверы канцерогенеза. В то же время во многих злокачественных новообразованиях обнаруживается патологическая активация ретроэлементов. Более того, порочный круг, когда дефицит онкосупрессора вызывает активацию ретроэлементов, способствующих инактивации других генов-супрессоров, специфичен не только для ТР53. Способностью негативно контролировать экспрессию ретроэлементов характеризуются и другие гены-супрессоры, которые содержат в своем составе горячие точки инсерционного мутагенеза и сами ретротранспозоны (которые способствуют рекомбинационным событиям). Сделано предположение, что патологическая взаиморегуляция ретроэлементов и онкосупрессоров является универсальным механизмом канцерогенеза при развитии как спорадических злокачественных новообразований, так и наследственных опухолевых синдромов. Наблюдаемая в 90 % образцов рака предстательной железы хромоплексия может отражать данные события, поскольку активированные ретроэлементы в канцерогенезе способствуют развитию комплексных хромосомных перестроек.

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