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Title: A genetic screen identifies novel regulators of the senescence-associated secretory phenotype
Author: Georgilis, Athena Eugenia
ISNI:       0000 0004 7656 9826
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Cellular senescence is a stable cell-cycle arrest induced by ageing or many stresses such as oncogene activation. Oncogene-Induced Senescence (OIS) is an intrinsic tumour suppressive mechanism but also has numerous extrinsic functions mediated by the senescence-associated secretory phenotype (SASP). Although the SASP attracts the immune system to clear damaged cells it can also promote cancer growth and age-associated systemic inflammation. Consequently, the SASP has been considered a potential therapeutic target. However, a better understanding of the molecular pathways regulating the complex secretome of senescent cells is necessary before designing therapeutic interventions. In this work, we set up and carried out an siRNA screen for genes regulating the SASP during OIS. By screening siRNAs targeting 8,352 genes, 84 novel regulators of IL-8 and IL-6 were found. We further interrogated their effect on levels of p16INK4a, p21Cip1 and BrdU incorporation. 49 genes were found to specifically regulate the SASP without affecting other senescence features. Combining the siRNA screening system with global transcriptome profiling for 38 of these genes revealed common pathways with a potential role in regulating the SASP. One of the candidates was the splicing factor PTBP1. PTBP1 depletion blunted the induction of several SASP factors without affecting the senescence growth arrest. The altered SASP produced upon PTBP1 depletion had distinct properties. For example, it decreased the ability to transmit senescence but retained the ability to attract natural killer cells. Mechanistically, during senescence, PTBP1 promoted exon skipping of several mRNAs involved in intracellular protein trafficking. Future work will aim at fully understanding the role of PTBP1 during senescence. Our data so far suggest the feasibility of targeting PTBP1 to specifically manipulate the SASP while maintaining the ability of inducing cell cycle arrest as a potential strategy to target inflammation-driven tumourigenesis.
Supervisor: Gil, Jesús Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral