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When p53 needs p73 to be functional - forced p73 expression induces nuclear accumulation of endogenous p53 protein
David Goldschneider1, Etienne Blanc, Gilda Raguenez
1Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8126, Institut Gustave Roussy, 94805 Villejuif Cedex, France.
Abstract:
In human neuroblastoma (NB), wild type p53 protein does not elicit its archetypal human tumor suppressive activity so far described. To elucidate this alteration, substantial investigations using NB cell lines have underscored p53 protein nuclear localization defect and/or inappropriate conformation, but no definitive evidence has been provided so far. p73, the first homologue of the p53 gene, locates at the 1p36.3 locus, which is known to be deleted in various human tumors including NB. Unlike p53 mRNA, which specifies a single protein, p73alpha mRNAs encode two types of isoform (TAp73alpha and DeltaNp73alpha) resulting from the use of two different promoters, and eliciting or lacking NH(2)-terminal transactivation domain, respectively. DeltaNp73alpha inhibits p53 pro-apoptotic function in murine developing neurons and is abundantly expressed in human undifferentiated NB tumors. However, critical issues have been raised regarding p73alpha isoform roles, and their possible link to p53 are yet to be clarified in human NB using adenoviral infection approach.
Insights
In human neuroblastoma, wild type p53 tumor suppressor activity is altered. The p73alpha isoform, DeltaNp73alpha, may inhibit p53 function, requiring further study in neuroblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Wild type p53 tumor suppressive activity is often lost in human neuroblastoma (NB).
- Previous studies suggest p53 nuclear localization defects or conformational issues in NB cell lines, but lack definitive proof.
- The p73 gene, a homolog of p53, is located at 1p36.3, a region frequently deleted in NB and other human tumors.
Purpose of the Study:
- To investigate the role of p73alpha isoforms in human neuroblastoma.
- To clarify the relationship between p73alpha isoforms and p53 function in human NB.
- To determine if DeltaNp73alpha inhibits p53 pro-apoptotic activity in human neuroblastoma.
Main Methods:
- Utilizing adenoviral infection in human neuroblastoma models.
- Analyzing p73alpha isoform expression and function.
- Investigating the impact of p73alpha isoforms on p53 activity.
Main Results:
- p73alpha mRNAs encode two isoforms: TAp73alpha and DeltaNp73alpha.
- DeltaNp73alpha lacks an N-terminal transactivation domain and inhibits p53 pro-apoptotic function in murine neurons.
- DeltaNp73alpha is highly expressed in human undifferentiated NB tumors.
Conclusions:
- The precise roles of p73alpha isoforms in human NB remain to be fully elucidated.
- Further research is needed to clarify the link between p73alpha isoforms and p53 in human neuroblastoma.
- Adenoviral infection approaches may provide critical insights into these interactions.