Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G₁/S transition in opposition to p18^INK4c and p27^Kip1

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 naïve mature B cells, which are naturally arrested in G₀/G₁ 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 G₁ 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-κB, 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 G₁ 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.

• BAFF
• cyclin D2
• cyclin E
• cyclin-dependent kinase
• B cell receptor signaling