Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1.
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.
Huang
Xiangao
X
Department of Pathology and Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Di Liberto
Maurizio
M
Cunningham
Adam F
AF
Kang
Lin
L
Cheng
Shuhua
S
Ely
Scott
S
Liou
Hsiou-chi
HC
Maclennan
Ian C M
IC
Chen-Kiang
Selina
S
D000818:Animals; D000906:Antibodies / Q000276:immunology; D053264:B-Cell Activating Factor; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D056742:Cyclin D2; D019927:Cyclin E / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase; D006706:Homeostasis; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; D053264:B-Cell Activating Factor; C486196:Ccnd2 protein, mouse; C493961:Cdkn1b protein, mouse; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D019927:Cyclin E; D050763:Cyclin-Dependent Kinase Inhibitor p18; D016213:Cyclins; D008565:Membrane Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases