Abstract 802: The inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis

Abstract

Abstract Hemangioma is the most frequent vascular tumor of early childhood. However, the mechanism leading to their development, progression and maintenance has remained unclear. In this study, we generated an endothelial-specific PyMT-expressing transgenic (Tg) mouse (Tie2-PyMT) that spontaneously develop hemangioma. Using Tie2-PyMT transgenic mice and bEnd.3 cells, an PyMT induced mouse brain endothelial cell line idicates that the direct expression of PyMT gene in vascular endothelial cells leads to rapid cell proliferation and hemangioma development. An interaction between the core AC dimer of protein phosphatase 2A (PP2A) and PyMT, but not B regulatory subunit was verified both in hemangioma endothelial cells of Tie2-PyMT Tg mice and bEnd.3 cells by immunoprecipitation. Whereas in endothelial cells of Tg negative mice and PyMT silenced bEnd.3 cells, the B regulatory subunit binds to the core AC dimer of PP2A. PyMT binding to PP2A led to the inactivation of PP2A phosphatases and subsequently activates its downstream ERK1/2 and AKT pathway, which may be responsible for the proliferative effect of PyMT on vascular endothelial cells. Moreover, the effect of PyMT on PP2A phosphatases activity could be rescued by Okadaic acid (OA), a specific inhibitor of PP2A. Treamtment of Tie2-PyMT transgenic mice with the PP2A activator, FTY720, significantly delayed hemangiomagenesis in this model. Furthermore, PP2A complex composition and its phosphatases activity were also examined in patient hemangioma specimens. Consisten with the animal model, a decreased PP2A phosphatases activity and the dissociation of B subunit from the PP2A core dimer were observed. These findings suggest that the inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis. Citation Format: Qin Xu, Furong Xie. The inactivation of PP2A caused by the replacement of its regulatory subunit plays a crucial role in the hemangiomagenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 802. doi:10.1158/1538-7445.AM2015-802