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TAp73 and ΔTAp73 isoforms show cell-type specific distributions and alterations in cancer
Vaclav Hrabal1,2, Michaela Stenckova3, Filip Zavadil Kokas3
1Research Center for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 656 53, Czech Republic. vaclav.hrabal@mou.cz.
Abstract:
TP73 is a member of the TP53 gene family and produces N- and C-terminal protein isoforms through alternative promoters, alternative translation initiation and alternative splicing. Most notably, p73 protein isoforms may either contain a p53-like transactivation domain (TAp73 isoforms) or lack this domain (ΔTAp73 isoforms) and these variants have opposing or independent functions. To date, there is a lack of well-characterised isoform-specific p73 antibodies. Here, we produced polyclonal and monoclonal antibodies to N-terminal p73 variants and the C-terminal p73α isoform, the most common variant in human tissues. These reagents show that TAp73 is a marker of multiciliated epithelial cells, while ΔTAp73 is a marker of non-proliferative basal/reserve cells in squamous epithelium. We were unable to detect ΔNp73 variant proteins, in keeping with recent data that this is a minor form in human tissues. Most cervical squamous cell carcinomas (79%) express p73α, and the distribution of staining in basal cells correlated with lower tumour grade. TAp73 was found in 17% of these tumours, with a random distribution and no association with clinicopathological features. These data indicate roles for ΔTAp73 in maintaining a non-proliferative state of undifferentiated squamous epithelial cells and for TAp73 in the production of differentiated multiciliated cells.
Insights
New antibodies reveal distinct roles for p73 protein isoforms in epithelial cells. TAp73 marks multiciliated cells, while ΔTAp73 marks non-proliferative basal cells, with implications for squamous cell carcinomas.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- TP73, a member of the TP53 gene family, generates diverse protein isoforms (TAp73 and ΔTAp73) with distinct functions.
- A lack of well-characterized isoform-specific antibodies has hindered the study of p73 protein functions.
- Understanding p73 isoform roles is crucial for comprehending epithelial cell differentiation and cancer development.
Purpose of the Study:
- To develop and validate novel antibodies for specific detection of N-terminal p73 variants and the p73α isoform.
- To investigate the cellular localization and potential roles of TAp73 and ΔTAp73 isoforms in normal squamous epithelium.
- To examine the expression patterns of p73 isoforms in cervical squamous cell carcinomas and their correlation with clinicopathological features.
Main Methods:
- Production of polyclonal and monoclonal antibodies targeting N-terminal p73 variants and the p73α isoform.
- Immunohistochemical analysis to determine the expression and localization of p73 isoforms in human tissues and cervical cancer samples.
- Correlation analysis between p73 isoform expression and tumor grade in cervical squamous cell carcinomas.
Main Results:
- Developed specific antibodies for N-terminal p73 variants and the p73α isoform.
- TAp73 identified as a marker for multiciliated epithelial cells, whereas ΔTAp73 marks non-proliferative basal/reserve cells in squamous epithelium.
- p73α expressed in 79% of cervical squamous cell carcinomas, with basal cell staining correlating with lower tumor grade; TAp73 found in 17% without clinicopathological association.
- ΔNp73 variant proteins were not detected, consistent with its minor form status in human tissues.
Conclusions:
- ΔTAp73 plays a role in maintaining the non-proliferative state of undifferentiated squamous epithelial cells.
- TAp73 is involved in the production of differentiated multiciliated cells.
- p73 isoform expression patterns in cervical cancer suggest potential roles in tumor progression and grade.
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