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

X Xiangao Huang, M DiLiberto, Adam Cunningham, L Kang, S Cheng, S Ely, H Liou, Ian MacLennan, S Chen-Kiang

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)


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 languageEnglish
Pages (from-to)17789-94
Number of pages6
JournalNational Academy of Sciences. Proceedings
Issue number51
Early online date10 Dec 2004
Publication statusPublished - 21 Dec 2004


  • 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


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