Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.686574
Title: Characterisation of novel post-translational modulators of p53
Author: Rada, Miran Madhar
ISNI:       0000 0004 5919 5404
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2016
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Abstract:
p53 is a tumour suppressor protein that has a crucial role in cellular responses to stress signals. p53 regulates a wide range of cellular functions that cover cell cycle arrest, apoptosis, gene repair, metabolism, fertility, cellular reprogramming and autophagy, among others. p53 regulation is a complex process that occurs via different mechanisms, including post-translational modifications (PTMs). The PTMs of p53 are achieved through various modulators. Here, we demonstrate the regulation of p53 through PTM by Burton’s Tyrosine Kinase (BTK), and Euchromatic histone-lysine N-methyltransferase 2 (G9a). We found that BTK expression is induced in response to DNA damage. Consecutively, BTK phosphorylates both p53 and MDM2, which results in p53 stabilization and increase in activity. Additionally, our experiments showed that BTK-mediated phosphorylation of p53 regulate other PTMs of p53. Specifically, BTK inhibits MDM2-dependent p53 ubiquitination, whereas augments both SET9-mediated K372 methylation, and CBP-mediated K373 acetylation. As a consequence, BTK enhances up-regulation of p53 stability, nuclear localization, and activity. On the other hand, we examined the effect of different forms of G9a on p53 activity, and we showed that they differentially regulate p53. The activity of p53 is enhanced by short isoform of human G9a (hG9a(S)), while we demonstrated the opposite effect d for mouse G9a (mG9a). In addition, the function of hG9a(S) towards p53 does not depend on K373-methylation. We propose that hG9a(S) acts as a coactivator of the p53-CBP interaction. Thus, our data suggest that both BTK and G9a play an important role in p53 regulation using both post-translational modification.
Supervisor: Macip, Salvador Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.686574  DOI: Not available
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