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1.
Proc Natl Acad Sci U S A ; 105(13): 5177-82, 2008 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-18362329

RESUMEN

The giant cytosolic protease tripeptidyl peptidase 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 dysregulation of NF-kappaB. 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.


Asunto(s)
Envejecimiento/inmunología , Apoptosis/inmunología , Serina Endopeptidasas/deficiencia , Serina Endopeptidasas/metabolismo , Aminopeptidasas , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Fibroblastos , Eliminación de Gen , Linfopenia/enzimología , Linfopenia/genética , Linfopenia/patología , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Fenotipo , Serina Endopeptidasas/genética , Linfocitos T/citología , Linfocitos T/enzimología , Linfocitos T/inmunología , Timo/citología , Timo/enzimología , Timo/inmunología , Proteína p53 Supresora de Tumor/metabolismo
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