Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27 Kip1 Academic Article uri icon

Overview

MeSH Major

  • Cell Cycle
  • Cell Cycle Proteins
  • Homeostasis
  • Membrane Proteins
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins

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.

publication date

  • December 21, 2004

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC535425

Digital Object Identifier (DOI)

  • 10.1073/pnas.0406111101

PubMed ID

  • 15591344

Additional Document Info

start page

  • 17789

end page

  • 94

volume

  • 101

number

  • 51