title: Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice.
abstract: 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.
authors: Clinic for Radiotherapy and Department of Experimental Anaesthesiology, University Hospital Freiburg, 79106 Freiburg, Germany.
authors: Jisen
authors: J
authors: Huai
authors: Elke
authors: E
authors: Firat
authors: Ahmed
authors: A
authors: Nil
authors: Daniele
authors: D
authors: Million
authors: Simone
authors: S
authors: Gaedicke
authors: Benoit
authors: B
authors: Kanzler
authors: Marina
authors: M
authors: Freudenberg
authors: Peter
authors: P
authors: van Endert
authors: Gabriele
authors: G
authors: Kohler
authors: Heike L
authors: HL
authors: Pahl
authors: Peter
authors: P
authors: Aichele
authors: Klaus
authors: K
authors: Eichmann
authors: Gabriele
authors: G
authors: Niedermann
mesh_terms: D000375:Aging / Q000276:immunology*; D000626:Aminopeptidases; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005347:Fibroblasts; D017353:Gene Deletion; D008231:Lymphopenia / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases