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Transcriptomic signatures of the INK4A/ARF locus in senescence regulation
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Orientador(es)
Resumo(s)
Cellular senescence is a stable cell cycle arrest that can be induced by a variety of stress signals, to avoid
further genomic instability and accumulation of DNA damage. However, senescent cells tend to
accumulate with age, creating a tissue microenvironment that is permissive to the development or
progression of cancer. The INK4A/ARF locus is one of the most frequently mutated sites in human
cancers and encodes two protein isoforms, p16 and ARF, both involved in cell cycle arrest, respectively
through the p16/Rb and p53/p21 pathways.
The focus of this project was studying senescence by analysing RNA sequencing data obtained from a
dataset including senescent samples induced with different stimuli.
We were able to distinguish between non-senescent and senescent conditions by estimating p16 and
ARF transcript expression levels. We identified genes that may be associated with p16 and ARF,
although some of them had already been described as having a role in senescence regulation, such as
the SASP factor GDF15, the long non-coding RNA MIAT, or even transcription factors previously
associated specifically with INK4A/ARF, for instance, EZH2 and SP1.
We have also identified two other gene candidates that may be associated with p16 and ARF, namely
MEIS2 a transcription factor previously known to enhance effectiveness of different anti-cancer drugs
when downregulated in a multiple myeloma human cell line. And also, KRTAP2-3, previously found to
inhibit proliferation and increasing migration of oral cancer cells via induction of epithelial to
mesenchymal transition. These findings agree with recent studies that have shown that senescent cells
can contribute to metastatic dissemination and colonization.
The pathways we found to be associated with either p16 or ARF, namely related to immune response,
cell cycle arrest, metabolic deregulation, and epithelial to mesenchymal transition, could represent
potential targets for senolytic therapies in the context of ageing diseases and cancer.
Descrição
Tese de mestrado, Bioinformática e Biologia Computacional , 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Senescência INK4A/ARF Sequenciação de RNA Cancro Teses de mestrado - 2024