Molecular and functional characterisation of the anti-apoptotic TA-p73 epsilon isoform in response to DNA damage The complexity of p73 is strictly related to the fact that it is expressed in the cells as several splice variants. Alternatively spliced C-terminus variants of p73 transcripts are expressed both in normal and tumour cells and exhibit different transcription activities. The expression of the different p73 C-terminus isoforms was shown to be different in different cell types and seems to be correlated to some extent to cancer progression. Taken together, all these data suggest that the role of p73 can not be defined without taking into account not only the different isoforms but also the cellular context in which they are analysed. p73 epsilon, which lacks exons 11 and 13, is an isoform still poorly characterised, it has been described as a weak inducer of apoptotic genes as well as a potential suppressor of this pathway depending on inter-variant connection with the other pro-apoptotic p73 isoforms. According to those data p73, epsilon seems to have an important role in carcinogenesis, we report that p73 epsilon is up-regulated in certain cancer cell types upon specific stress agents and acts as a dominant negative for p53-mediated apoptosis Interestingly, we observed by using chromatin immunoprecipitation technique that p73 epsilon is able to bind p53 target promoters but it is unable to transactivate them. We can observe that epsilon p73 isoform can not lead to apoptosis after its induction and also it is not able to arrest the cells in G1 even in the presence of treatments. Through the analysis of the role of p73 epsilon, the anti-apoptotic role of epsilon in cells with active p53 was demonstrated and for the first time the mechanism for the function of p73 that lies in mutually exclusive binding with p53 for pro-apoptotic promoters was demonstrated. This study underlines the evidence that p73 epsilon, which is up-regulated upon certain therapeutic agents in some cancer cell lines, may serve as survival advantage to anti-cancer therapy.
|Titolo:||Molecular and functional characterisation of the optotic TA-P73 isoform in response to DNA damage|
|Supervisori e coordinatori interni:||VILLA, MARIA LUISA|
|Data di pubblicazione:||2006|
|Settore Scientifico Disciplinare:||Settore MED/08 - Anatomia Patologica|
Settore MED/04 - Patologia Generale
|Citazione:||Molecular and functional characterisation of the optotic TA-P73 isoform in response to DNA damage ; Silvano Bosari, Maria Luisa Villa. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE BIOMOLECOLARI E BIOTECNOLOGIE, 2006. ((19. ciclo, Anno Accademico 2005/2006.|
|Appare nelle tipologie:||13 - Tesi di dottorato discussa entro ottobre 2010|