Mechanismy replikativní, chemicky a onkogeny indukované buněčné senescence

Košař, Martin

Cells continuously experience various forms of exogenous and endogenous stress stimuli. Cellular senescence, a state of permanent cell-cycle arrest, is a physiological response that prevents proliferation of damaged cells. It is an important tumor suppressive mechanism, because evading senescence in pre-malignant tumors leads to cancer progression. However, in the long term, senescence can also contribute to tissue aging. Our understanding of the causes and consequences of senescence can provide important insights into processes such as cancer development and aging and may help us design new therapeutic approaches. In the first part of my thesis, we investigated a relationship between two known tumor suppressor pathways, the DNA Damage Response (DDR) and the Alternative Reading Frame (ARF), in response to oncogenic insults. By using several mouse models, human clinical samples and cell culture models we showed, that ARF activation occurs at a later stage of tumor progression than activation of the DDR. Moreover, ARF activation requires a higher level (threshold) of oncogenic stress than DDR. Therefore, we proposed, that ARF represents a delayed and complementary barrier to tumor progression. Senescence-associated heterochromatin foci (SAHF) formation, representing pronounced changes in chromatin,...

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