Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1

Research output: Contribution to journalArticle

Authors

  • X Xiangao Huang
  • M DiLiberto
  • L Kang
  • S Cheng
  • S Ely
  • H Liou
  • S Chen-Kiang

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)17789-94
Number of pages6
JournalNational Academy of Sciences. Proceedings
Volume101
Issue number51
Early online date10 Dec 2004
Publication statusPublished - 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