Unlocking the role of p63 gene splicing in epithelial cancer development through stem cell activation

Title : Unlocking the role of p63 gene splicing in epithelial cancer development through stem cell activation

Abstract:

The transcription factor p63 is part of the p53 tumor suppressor family and is uniquely responsible for regulating the proliferative potential of stem cells in epithelial tissues. While studies have shown that p63 can exhibit both tumor-suppressive and oncogenic properties in vitro, studies using knockout and transgenic mouse models have not linked p63 to tumor suppression or oncogenesis in vivo. Despite the rarity of p63 mutations in cancer, our previous study demonstrated a strong association between the splicing out of exon 4 of the p63 gene and epithelial tumor formation. Specifically, the loss of exon 4 leads to the activation of progenitor cells in epithelial tissues, contributing to cancer development. In experiments with mice lacking exon 4 of the p63 gene, it was found that heterozygous mutants developed normally but displayed increased hyperplasia in certain epithelial tissues when exposed to carcinogens or oncogenic stimuli. Additionally, clonogenic culture of epithelia, originally developed for skin grafts, has shown that progenitor cells in mutant epithelia exhibit hyperproliferation compared to their wild type counterparts. These findings collectively underscore the critical role of p63 in tumor suppression in vivo and emphasize the importance of splicing rather than gene mutation in compromising epithelial progenitor cell activity, ultimately leading to the development of precancerous conditions and potentially to aggressive cancers such as squamous cell carcinomas.

Audience Take Away Notes:

• Abnormal splicing rather than gene mutation leads to p63-associated cancers
• This is the first mouse model of epithelial cancer induced by p63 dysregulation
• The Δ4p63 model supports two-step carcinogenesis of epithelia
• Probes (e.g. antibodies) for Δ4p63 can serve as novel diagnostic tools for epithelial cancers
• Our study suggests dysregulation of stem cells can cause cancers in epithelia

Biography:

Dr. Keshia Pitt received her undergraduate degree in biology from St. John’s University in Queens, New York and her doctorate from Boston University School of Medicine in Boston, Massachusetts. Her dissertation research in Dr. Makoto Senoo’s lab characterized a novel splice variant of the transcription factor p63 that leads to precancerous hyperproliferation of epithelial stem cells.