QPP (Quiescent cell _.Proline di-_Peptidase), also termed DPP2/7, is a vesicular protease that cleaves di- peptides from the N-terminus of proteins, thereby impacting their half-life and/or receptor specificity. While the full functional profile of this enzyme is far from understood, in vitro experiments demonstrate that QPP is a major regulator of the Go quiescence program in primary lymphocytes and neuronal cells. The primary objective of this renewal application is to analyze the mechanism of QPP-mediated survival in resting lymphocytes.
Aim I : The most direct approach to define the functional role of QPP is to generate a mutant mouse deficient in QPP. Since previous attempts to derive conventional QPP# mice were curbed by embryonic lethality, we propose a novel alternative to generate the mutant mouse, utilizing the Cre/IoxP recombinase system that allows conditional and inducible genome alterations.
Aim I 1"""""""" Inhibition of QPP advances quiescent lymphocytes into cell cycle, leading to upregulation of c- Myc and p53 and finally apoptosis induction. Thus, it is postulated that QPP enzyme activity is required for maintaining the Go program. To test this hypothesis, the control of expression and mechanism of action of QPP will be delineated. Special emphasis will be given to LKLF and STAT5, two transcription factors that are implicated in positive and negative regulation of QPP expression, respectively. Furthermore, the role of c-Myc and p53 in the apoptosis pathway will be analyzed.
Aim II 1: To fully understand the Go survival program in eukaryotic cells, it is essential to define the physiological substrate(s) of QPP. Since this is the most ambitious project, various approaches will be used to reach this goal, including the screen of combinatorial dipeptide substrate libraries, the structural comparison of human and murine QPP with that of DPP4, and the isolation of a physiological substrate(s) by affinity matrix chromatography. Collectively, these studies will augment our limited understanding of the constitutive Go survival program in eukaryotic cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043469-08
Application #
7162147
Study Section
Immunobiology Study Section (IMB)
Program Officer
Palker, Thomas J
Project Start
1999-03-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2008-12-31
Support Year
8
Fiscal Year
2007
Total Cost
$300,573
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Mele, Deanna A; Sampson, James F; Huber, Brigitte T (2011) Th17 differentiation is the default program for DPP2-deficient T-cell differentiation. Eur J Immunol 41:1583-93
Danilov, Alexey V; Danilova, Olga V; Brown, Jennifer R et al. (2010) Dipeptidyl peptidase 2 apoptosis assay determines the B-cell activation stage and predicts prognosis in chronic lymphocytic leukemia. Exp Hematol 38:1167-77
Mele, Deanna A; Bista, Pradeep; Baez, Diana Velez et al. (2009) Dipeptidyl peptidase 2 is an essential survival factor in the regulation of cell quiescence. Cell Cycle 8:2425-34
Rockwell, Karen R; Huber, Brigitte T (2009) Biologically distinct conformations of Bcl-x can be resolved using 2D isoelectric focusing. Mol Immunol 46:1605-12
Danilova, Olga V; Tai, Albert K; Mele, Deanna A et al. (2009) Neurogenin 3-specific dipeptidyl peptidase-2 deficiency causes impaired glucose tolerance, insulin resistance, and visceral obesity. Endocrinology 150:5240-8
Bista, Pradeep; Mele, Deanna A; Baez, Diana Velez et al. (2008) Lymphocyte quiescence factor Dpp2 is transcriptionally activated by KLF2 and TOB1. Mol Immunol 45:3618-23
Danilova, Olga; Li, Bei; Szardenings, A Katrin et al. (2007) Synthesis and activity of a potent, specific azabicyclo[3.3.0]-octane-based DPP II inhibitor. Bioorg Med Chem Lett 17:507-10
Danilov, Alexey V; Klein, Andreas K; Lee, Henry J et al. (2005) Differential control of G0 programme in chronic lymphocytic leukaemia: a novel prognostic factor. Br J Haematol 128:472-81
Denis, Maria C; Huber, Brigitte T (2003) Native and recombinant interleukin-2, two functionally distinct molecules. Mol Immunol 40:279-86
Seward, Robert J; von Haller, Priska D; Aebersold, Ruedi et al. (2003) Phosphorylation of the pro-apoptotic protein Bim in lymphocytes is associated with protection from apoptosis. Mol Immunol 39:983-93

Showing the most recent 10 out of 15 publications