Trp63, also known as Transformation-related protein 63, is a predominant member of the Trp53 family. It contributes to epithelial differentiation and is involved in various pathways such as Wnt and Notch signaling [2]. It features two distinct promoters encoding two major TRP63 isoforms with functions linked to cell cycle arrest, apoptosis, survival, and epithelial-mesenchymal transition (EMT) [2]. Genetic models like Trp63CreERT2-labeled cells are valuable for studying its functions in vivo.

In lung-related studies, Trp63CreERT2-labeled ectopic basal cells (EBCs) do not exhibit alveolar regeneration potential, but when tamoxifen is administrated post-viral infection, Trp63CreERT2 labels islands of alveolar epithelial cells negative for EBC biomarkers [1]. Germline deletion of Trpm5 significantly increases the contribution of Trp63CreERT2-labeled cells to the alveolar epithelium [1]. In the skin, TRP63/TP63 loss accelerates skin tumorigenesis through activation of Wnt/β-catenin signaling [3]. In the liver, hepatic p63 (a product of Trp63) regulates glucose metabolism by repressing SIRT1 [4]. In esophageal development and malignancy, deletion of p63 results in extensive neuroendocrine differentiation, and up-regulation of the major p63 isoform ΔNp63α promotes squamous transdifferentiation [5].

In conclusion, Trp63 is crucial for epithelial differentiation and plays diverse roles in various biological processes. Mouse models with Trp63 gene knockout or conditional knockout have revealed its significance in diseases such as lung injury-related regeneration, skin tumorigenesis, glucose metabolism-related disorders, and esophageal malignancies. These studies help in understanding the biological functions of Trp63 and provide insights into potential therapeutic strategies for related diseases.