cytosolic sequestration of prep1 influences early stages of t cell development胞质封存prep1影响t细胞发展的早期阶段.pdfVIP

Cytosolic Sequestration of Prep1 Influences Early Stages of T Cell Development 1¤ 1 2 1,3 Dmitry Penkov , Martina Palazzolo , Anna Mondino *, Francesco Blasi * ` 1 Molecular Genetics Unit, San Raffaele Scientific Institute and Universita Vita Salute San Raffaele, Milan, Italy, 2 Lymphocyte Activation Unit, San Raffaele Scientific ` Institute and Universita Vita Salute San Raffaele, Milan, Italy, 3 Institute of Molecular Oncology, Milan, Italy Abstract Objective: Prep1 and Pbx2 are the main homeodomain DNA-binding proteins of the TALE (three amino acid loop extension) family expressed in the thymus. We previously reported reduced Pbx2 expression and defective thymocyte maturation in Prep1 hypomorphic mice. To further investigate the role of this homeodomain DNA-binding protein in T cell development, we generated transgenic mice expressing the N-terminal fragment of Pbx1 (Pbx1NT) under the control of the Lck proximal promoter. Principal Findings: Pbx1NT causes Prep1 cytosolic sequestration, abolishes Prep1-dependent DNA-binding activity and results in reduced Pbx2 expression in developing thymocytes. Transgenic thymi reveal increased numbers of CD42 CD82 CD442 (DN3 and DN4) thymocytes, due to a higher frequency of DN2 and DN4 Pbx1NT thymocytes in the S phase. Transgenic thymocytes however do not accumulate at later stages, as revealed by a normal representation of CD4/CD8 double positive and single positive thymocytes, due to a higher rate of apoptotic cell death of DN4 Pbx1NT thymocytes. Conclusion: The results obta