Abstract
Cell-cycle entry is critical for homeostatic control in physiologic response of higher organisms but is not well understood. The antibody response begins with induction of naive mature B cells, which are naturally arrested in G(0)/G(1) phase of the cell cycle, to enter the cell cycle in response to antigen and cytokine. BLyS (BAFF), a cytokine essential for mature B cell development and survival, is thought to act mainly by attenuation of apoptosis. Here, we show that BLyS alone induces cell-cycle entry and early G(1) cell-cycle progression, but not S-phase entry, in opposition to the cyclin-dependent kinase inhibitors p18(INK4c). Independent of its survival function, BLyS enhances the synthesis of cyclin D2, in part through activation of NF-kappaB, as well as CDK4 and retinoblastoma protein phosphorylation. By convergent activation of the same cell-cycle regulators in opposition to p18(INK4c), B cell receptor signaling induces cell-cycle entry and G(1) progression in synergy with BLyS, but also DNA replication. The failure of BLyS to induce S-phase cell-cycle entry lies in its inability to increase cyclin E and reduce p27(Kip1) expression. Antagonistic cell-cycle regulation by BLyS and p18(INK4c) is functionally linked to apoptotic control and conserved from B cell activation in vitro to antibody response in vivo, further indicating a physiologic role in homeostasis.
Original language | English |
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Pages (from-to) | 17789-94 |
Number of pages | 6 |
Journal | National Academy of Sciences. Proceedings |
Volume | 101 |
Issue number | 51 |
Early online date | 10 Dec 2004 |
DOIs | |
Publication status | Published - 21 Dec 2004 |
Keywords
- Animals
- Antibodies
- B-Cell Activating Factor
- Cell Cycle
- Cell Cycle Proteins
- Cell Survival
- Cells, Cultured
- Cyclin D2
- Cyclin E
- Cyclin-Dependent Kinase 4
- Cyclin-Dependent Kinase Inhibitor p18
- Cyclin-Dependent Kinase Inhibitor p27
- Cyclin-Dependent Kinases
- Cyclins
- G1 Phase
- Homeostasis
- Membrane Proteins
- Mice
- Mice, Knockout
- NF-kappa B
- Proto-Oncogene Proteins
- S Phase
- Signal Transduction
- Tumor Necrosis Factor-alpha
- Tumor Suppressor Proteins