Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice

作者：Huai Jisen; Firat Elke; Nil Ahmed; Million Daniele; Gaedicke Simone; Kanzler Benoit; Freudenberg Marina; van Endert Peter; Kohler Gabriele; Pahl Heike L; Aichelel Peter; Eichmann Klaus; Niedermann Gabriele^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(13): 5177-5182.

DOI：10.1073/pnas.0801413105

• apoptosis
• senescence
• T lymphocytes
• tripepticlyl peptidase II

The giant cytosolic protease tripepticlyl pepticlase II (TPPII) has been implicated in the regulation of proliferation and survival of malignant cells, particularly lymphoma cells. To address its functions in normal cellular and systemic physiology we have generated TPPII-deficient mice. TPPII deficiency activates cell type-specific death programs, including proliferative apoptosis in several T lineage subsets and premature cellular senescence in fibroblasts and CD8+ T cells. This coincides with up-regulation of p53 and dysiregulation of NF-kappa B. Prominent degenerative alterations at the organismic level were a decreased lifespan and symptoms characteristic of immunohematopoietic senescence. These symptoms include accelerated thymic involution, lymphopenia, impaired proliferative T cell responses, extramedullary hematopoiesis, and inflammation. Thus, TPPII is important for maintaining normal cellular and systemic physiology, which may be relevant for potential therapeutic applications of TPPII inhibitors.

• 出版日期2008-4-1