Abstract 3919: Potential roles of oncogenic ΔNP63α during bone and bone cancer formation

Abstract

Abstract P63 belongs to the P53 tumor suppressor gene family. Due to its alternative promoter usage and splicing, p63 consists of two major subtypes (TAp63 and ΔNp63) and six different isoforms (TAp63α, β, or γ and ΔNp63α, β, or γ). These isoforms have been shown to play distinct biological functions in cancer and development. P63, especially the ΔNp63α variant, has been suggested to play an oncogenic role in cancer progression, including bone-related tumors such as giant cell tumor of bone and osteosarcoma. Interestingly, P63 has previously been shown to be an essential player for limb development. This raises the possibility that there might be a specific mechanism linking P63 regulation of bone and bone cancer formation. The type X collagen gene (Col10a1) is a specific marker of hypertrophic chondrocytes during endochondral bone formation. As a matrix protein, type X collagen also functions as a regulatory molecule that affects chondrocyte mineralization, apoptosis, and angiogenesis. Therefore, transcriptional regulators critical for Col10a1 expression are also expected to affect the apoptotic pathway that occurs during bone cancer formation. By real-time RT-PCR and proteomic approaches using a MCT cell model, we demonstrate here that P63 contributes to regulation of Col10a1 expression in vitro. We also have data which supports that Runx2 regulates cell-specific Col10a1 expression via the Runx2 binding sites found within the Col10a1 cis-enhancer. This is intriguing since p63 was previously shown to interact with Runx2 by yeast two-hybrid approach. Moreover, we have generated a mouse model in which Runx2 was driven by the cell-specific Col10a1 control element. Our preliminary results showed that these Col10a1-Runx2 transgenic mice have enhanced Runx2 and Col10a1 expression, a longer hypertrophic zone, altered chondrocyte maturation, apoptosis, and disturbed ossification. These results suggest the decreased apoptotic activity mediated by Runx2, whereas elevated Runx2 expression has been associated with osteosarcoma development and chondrosarcoma progression. To address the potential in vivo relevance of P63 on bone and cancer formation, we have established Col10a1-ΔNp63α transgenic mouse lines using the same Col10a1 control element. Characterization of these transgenic mice will allow us to study if this oncogenic P63 isoform regulates Col10a1 expression in vivo and if this regulation is within the network regulating both bone and bone cancer formation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3919.