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Mutant p53 subverts p63 control over KLF4 expression in keratinocytes
N Cordani1, S Pozzi, E Martynova
1Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi di Milano Via Celoria 26, Milano, Italy.
Oncogene
|October 26, 2010
Summary
p63 protein suppresses KLF4 in normal skin cells, but mutations in p53 can cause p63 to activate KLF4, promoting squamous cell carcinoma growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Dermatology
Background:
- p63 is essential for stratified epithelial development and maintenance.
- KLF4 is critical for skin barrier function and cellular reprogramming.
- The interplay between p63 and KLF4 in keratinocytes is not fully understood.
Purpose of the Study:
- To elucidate the regulatory relationship between p63 and KLF4 in keratinocytes.
- To investigate the role of p53 mutations in modulating p63-KLF4 interactions.
Main Methods:
- RNA interference and overexpression studies.
- Chromatin immunoprecipitation assays.
- Reporter construct transfections and immunohistochemical analysis.
Main Results:
- p63 directly represses KLF4 in normal keratinocytes by binding to promoter regions.
- KLF4 expression is higher in upper skin layers and increases with keratinocyte differentiation.
- Mutant p53, in conjunction with p63 inactivation, represses KLF4, while p53 mutants can activate KLF4.
- Increased coexpression of KLF4 and mutant p53 is observed in squamous cell carcinomas.
Conclusions:
- p63's suppression of KLF4 is a growth-promoting mechanism in normal epidermis.
- Tumor-predisposing p53 mutations alter p63 binding to the KLF4 promoter, converting it into an activator.
- This mechanism highlights how p53 mutations can drive cancer by manipulating key developmental factors like KLF4.
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