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Published on: December 26, 2019
p73 and p63 regulate the expression of fibroblast growth factor receptor 3
A Emre Sayan1, Barbara D'Angelo, Berna S Sayan
1MRC Toxicology Unit, Lancaster Road, Hodgkin Building, Leicester LE1 9HN, UK. aes16@le.ac.uk
Abstract:
p53, p63 and p73 make a family of transcription factors that play a vital role in development and cancer. All p53 family members have more than one promoter producing Transactivating (TA) and Dominant Negative (DeltaN) isoforms and their mRNAs are subjected to extensive splicing at 3' end to produce multiple protein products. p53 is usually inactivated by point mutations during tumorigenesis, whereas the expression levels and p63 and p73 are modulated to give tumor cells a selective advantage. In this study, aiming to find novel targets of the p53 family members, we identified FGFR3 as a gene transcriptionally controlled by p63 and p73. FGFR3 has been implicated in development and tumor biology as activating mutations of this gene was described in skeletal disorders, non-invasive skin conditions and superficial bladder cancers. We found that TAp73, TAp63 and DeltaNp63 was capable of inducing FGFR3. siRNA mediated downregulation of DeltaNp63 decreased endogenous FGFR3 protein levels. Our findings of this new link between p53 family proteins and FGFR3 may help understanding the transition of superficial bladder cancers to an invasive phenotype.
Insights
The p53 family of transcription factors, including p63 and p73, regulates FGFR3 gene expression. This discovery offers insights into how superficial bladder cancers may become invasive.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The p53, p63, and p73 protein family are crucial transcription factors in development and cancer.
- These proteins exhibit multiple isoforms (Transactivating and Dominant Negative) and undergo extensive mRNA splicing.
- While p53 is often inactivated by mutation, p63 and p73 expression is modulated for tumor cell advantage.
Purpose of the Study:
- To identify novel target genes regulated by the p53 family members (p53, p63, p73).
- To investigate the role of p63 and p73 in controlling Fibroblast Growth Factor Receptor 3 (FGFR3) expression.
Main Methods:
- Investigated transcriptional control of FGFR3 by p63 and p73.
- Utilized siRNA-mediated downregulation to assess the impact of DeltaNp63 on endogenous FGFR3 protein levels.
Main Results:
- FGFR3 was identified as a gene transcriptionally controlled by p63 and p73.
- TAp73, TAp63, and DeltaNp63 isoforms were found to induce FGFR3 expression.
- Downregulation of DeltaNp63 using siRNA led to decreased endogenous FGFR3 protein levels.
Conclusions:
- Established a novel regulatory link between p53 family proteins (p63, p73) and FGFR3.
- Findings may elucidate the mechanism driving the transition of superficial bladder cancers to an invasive phenotype.
- Highlights the role of FGFR3 in development and tumor biology, with implications for skeletal disorders and skin conditions.
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