Abstract
The T cell costimulatory receptor 4-1BB enhances cell cycle progression and proliferation of CD8(+) T cells in both an IL-2-dependent and -independent manner. In these studies, 4-1BB costimulation was shown to increase cyclin D2, D3, and E expression, and concomitantly down-regulate the expression of the cyclin-dependent kinase inhibitor p27(kip1). 4-1BB increases cyclin D2 transcription via mitogen-activated/extracellular signal-regulated kinase-1/2 and LY294002-sensitive phosphatidylinositol 3-kinase (PI3K) signaling pathways. In addition, 4-1BB up-regulates cyclin D2 translation via PI3K/Akt/mammalian target of rapamycin (mTOR) pathways, presumably triggered by IL-2/IL-2 receptor ligation. The enhanced cyclin D2 and D3 expression initiates up-regulation of cyclin E expression and down-regulation of p27(kip1). Our results suggest a role for cyclin D2, D3, and E, and p27(kip1) proteins in the 4-1BB-mediated cell cycle progression of CD8(+) T cells in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD
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CD8-Positive T-Lymphocytes / cytology*
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CD8-Positive T-Lymphocytes / physiology*
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Cell Cycle
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Cell Cycle Proteins / genetics*
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Cell Division
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Cross-Linking Reagents
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Cyclin D2
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Cyclin D3
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Cyclin E / genetics
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / genetics*
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Gene Expression
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In Vitro Techniques
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Interleukin-2 / pharmacology
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MAP Kinase Signaling System
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Male
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Mice
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Mice, Inbred BALB C
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Nerve Growth Factor / physiology*
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Receptors, Tumor Necrosis Factor / physiology*
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Tumor Suppressor Proteins / genetics*
Substances
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Antigens, CD
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Ccnd2 protein, mouse
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Ccnd3 protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cross-Linking Reagents
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Cyclin D2
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Cyclin D3
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Cyclin E
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Cyclins
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Interleukin-2
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RNA, Messenger
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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Tnfrsf9 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27