Abstract
Most cells in the body are in a resting state and undergo cell cycle progression only upon growth factor stimulation or activation. while much research on proliferation and activation has been performed, very little about signals that maintain quiescent cells in G(0) is known, preventing cell cycle entry or apoptosis. In this study, the pathways of apoptosis induction in quiescent peripheral blood cells and fibroblasts mediated by inhibition or downregulation of Dipeptidyl Peptidase 2 (DPP2) have been explored. A decrease in DPP2 activity was found to cause resting cells to exit from G(0), accompanied by a decrease in p130, p27(Kip1) and p21(Cip1) protein levels. In addition, DPP2-inhibited or downregulated cells exhibit an increase in early G(1)/S progressors, with increases in the levels of retinoblastoma (pRb), p107 and cyclin D proteins. Furthermore, decrease of DPP2 activity leads to an increase in c-Myc and a decrease in Bcl-2, two events that have been associated with apoptosis induction. This apoptosis by DPP2 downregulation is prevented in p53(-/-) cells or by ectopic expression of proteins that suppress p53 or c-Myc activity. Thus, DPP2 is essential for maintaining lymphocytes and fibroblasts in G(0), and its inhibition results in apoptosis mediated by induction of c-Myc and p53.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology
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Butadienes / pharmacology
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Cyclin D
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Cyclins / metabolism
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism*
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Flavonoids / pharmacology
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Humans
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism*
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / metabolism
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Nitriles / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-myc / metabolism
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Resting Phase, Cell Cycle / drug effects
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Resting Phase, Cell Cycle / physiology
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Retinoblastoma Protein / metabolism*
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Retinoblastoma-Like Protein p107 / metabolism
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Tumor Suppressor Protein p53 / metabolism
Substances
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Butadienes
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Cyclin D
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Cyclins
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Enzyme Inhibitors
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Flavonoids
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MYC protein, human
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Nitriles
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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RBL1 protein, human
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Retinoblastoma Protein
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Retinoblastoma-Like Protein p107
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Tumor Suppressor Protein p53
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U 0126
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase Kinases
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
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dipeptidyl peptidase II
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one