Hudson, C.D.; (2005) The regulation of neuronal cell fate by the interaction of the Brn-3a transcription factors and the p73 family of proteins. Doctoral thesis , University of London.

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Abstract

The Brn-3a and Brn-3b POU transcription factors are expressed in the developing nervous system where Brn-3a is associated with sensory neuronal differentiation and survival. It has been shown that Brn-3a directly interacts with the p53 protein and this interaction resulted in differential regulation of gene targets which affect cell fate i.e. death or differentiation. The p53 related protein, p73, is involved in neuronal development and is expressed as multiple alternatively spliced C-terminal isoforms (TAp73a-£), and N-terminally deleted, dominant negative proteins (ANp73a-P) that show reciprocal function to the TA forms and p53. In this study we show that the Brn-3a/Brn-3b proteins also physically interacted with the p73 isoforms via the POU domain of Brn-3 and the region containing the OD domain of p73 and this interaction is modulated by the different C-terminals of the p73 isoforms. The effect of the Brn-3a/p73 interaction was tested on p53 target genes where co-expression of Brn-3a was shown to potentiate the transcriptional effect of TAp73 on the p2icn>1/Wafl promoter whilst antagonizing TAp73/p53 mediated activation of the pro-apoptotic genes box and noxa. Additionally Brn-3a uses a variety of different mechanisms to modulate the expression of different p53 target genes as well as playing a role in determining the selectivity of individual TAp73 members in controlling the expression of the bax promoter. In agreement with a functional effect, co-expression of Brn-3a and TAp73 increased cell cycle arrest and survival in the ND7 neuronal cell line, whereas co-expression of Brn-3a and ANp73 had no effect on cell cycle arrest but increased cell survival. Similar to p53, p73 (TA and AN) co-localised to a subset of Brn-3a positive neural crest cells (NCC) fated for a sensory lineage. Some of these Brn-3a/p73 co-expressing cells suggested a differentiated cell type and co-localization of TAp73 but not ANp73 with the differentiation marker NF-160, suggested that TAp73, like p53 is associated with differentiation of Brn-3a positive NCC effects of Brn-3a-p73/p53 co-expression was analysed in NCC cultured from Brn-3a-/- embryos showed significantly increased apoptosis upon induction of p53/p73 compared with WT cultures, suggesting that Brn-3a is necessary to overcome the p73/p53 apoptotic pathway. Thus, interaction with Brn-3a in sensory neurones may be critical for modulating p73/p53 mediated gene expression and hence cell fate.

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