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Title: Analysing the effect of co-expression of Brn-3a/POU4F1 transcription factor with p53 family proteins in the heart
Author: Fujita, R.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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The fate of cells is determined by a distinct group of transcription factors (TFs) which control the target gene expression in response to cellular stimuli during development and after injury. Moreover, TFs can physically interact with each other, thereby modifying target gene transcription for the fine­‐-tuning of cell fate determination depending on the specific cellular signals. The Brn­‐-3 family of TFs, B rn‐-­3aand Brn-­‐3b, was o riginallyisolated and characterised in the neurons of the central and peripheral nervous system, where they play a critical role in differentiation and cell survival during the nervous development. Studies have since shown that Brn­‐- 3TFs are expressed in the murine heart during cardiac development, however, the roles of these TFs in the heart following injury are yet to be elucidated. Further to the direct control of gene transcription, Brn-­‐3a also physically interacts with p53 and alters cellular response by modifying p53 target gene expression. Thus, up onco-­‐expression with p53, Brn -­‐3 aprotects neuronal cells from apoptosis and enhances survival by inhibiting p53­‐-mediated transcription of pro-¬‐ apoptotic prot einsBax and Noxa, while increasing expression of cell cycle arrest gene p21cip1/waf1 In this study, we investigated the potential role for Brn­‐-3a in protecting cardiomyocytes from p53-­‐mediated apoptosis following injurious stimuli such as ischemia. W efound that p53 a ndit spr o-­‐apoptotic target g enesBax, Noxa and Puma were markedly induced in the infarcted m yocardiumof the injured mouse heart by 1 week after permanent ischemia. In contrast, pro­‐-survival Brn-­‐3 awas upregulated in the non-­‐infarct, remote area of the heart, but interestingly, Brn-­‐3a was found to be downregulated in the infarcted tissues where upregulation of the pro-­‐apoptotic proteins was most evident. Importantly, immunostaining analysis revealed that Brn­‐-3a was co-¬‐ localised with p53 in a distinct region of myocardium bordering th einfarct and non­‐- infarct areas. Moreover, transfection studies indicated that Brn­‐-3a enhanced activity of p53 to activate thep21cip1/waf1 promoter in H9c2 cells. In conclusion, our results suggest that Brn­‐-3a is co­‐-expressed with p53 in a subpopulation o fcardiomyocytes following ischemic injury and that this pro-­‐survival TF may play a role in protecting cardiomyocytes from ischemia­‐-induced apoptosis through modulation of p53­‐-dependent transcription of apoptosis­‐-associated genes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available