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Title: Role of oncogene-induced senescence in thyroid carcinogenesis
Author: Vizioli, Maria Grazia
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2012
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Oncogene-induced senescence (OIS) is an irreversible G 1 cell cycle arrest triggered by aberrant expression of oncogenes. The arrest observed during senescence is implemented mainly through activation of p53 and the upregulation of the cyclin-dependent kinase (CDK) inhibitors, p16INK4a and p21cIPl. In vivo OIS may act as a barrier to neoplastic transformation, and bypass of OIS is a prerequisite for tumorigenesis. In this work the role of OIS in thyroid carcinogenesis was investigated by in combination of in vitro and in vivo approaches. We found that expression of different thyroid tumour-associated oncogenes (BRAF, RAS, RET and TRK) in primary human thyrocytes triggers senescence, as demonstrated by the presence of OIS hallmarks. For instance, cells appeared flatted and enlarged; they displayed senescence-associated B galactosidase activity (SA- B-Gal), senescence associated heterochromatic foci (SAHF), and high expression levels of the CDK inhibitors p 16INK4a and p21 CIPl and p53. Additionally, using RNA-interference strategy we directly assessed the individual contribution of p16INK4a in BRAFv6ooE-induced senescence. In our experimental setting the inactivation of p 16INK4a did not have any impact on oncogene- , induced senescence suggesting the possibility that p 16INK4amay cooperate with other factors in triggering senescence. A major consequence of oncogene activation is the secretion of a plethora of proteins ineluding growth factors, cytokines, and chemokines. Some of these secreted proteins are known to be regulators of OIS. For example, IGFBP7 is recently proposed as a mediator of BRAFV600E_induced senescence in melanocytes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available