Homeostatic cell-cycle control by BLyS:: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1
Homeostatic cell-cycle control by BLyS:: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1
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DOI：
10.1073/pnas.0406111101
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发表时间：
2004-12-21
影响因子：
11.1
通讯作者：
Chen-Kiang, S
中科院分区：
文献类型：
--
作者：
Huang, XG;Di Liberto, M;Chen-Kiang, S
细胞周期的进入对于高等生物生理反应中的稳态控制至关重要，但尚未得到很好的理解。抗体应答开始于诱导幼稚成熟B细胞，其在细胞周期的G（0）/G（1）期天然停滞，以响应抗原和细胞因子进入细胞周期。BLyS（BAFF）是一种成熟B细胞发育和存活所必需的细胞因子，被认为主要通过减弱细胞凋亡起作用。在这里，我们表明，BLyS单独诱导细胞周期进入和早期G，细胞周期的进展，但不是S期进入，在反对的细胞周期蛋白依赖性激酶抑制剂p18（INK 4c）。BLyS不依赖于其存活功能，部分通过激活NF-κ B以及CDK 4和视网膜母细胞瘤蛋白磷酸化来增强细胞周期蛋白D2的合成。通过与p18（INK 4c）相反的相同细胞周期调节剂的会聚激活，B细胞受体信号传导诱导细胞周期进入和G1进展，与BLyS协同，而且还诱导DNA复制。BLyS不能诱导S期细胞进入细胞周期的原因在于它不能增加cyclin E和减少p27（KiP 1）的表达。BLyS和p18（INK 4c）的拮抗性细胞周期调节在功能上与凋亡控制相关，并且从体外B细胞活化到体内抗体应答都是保守的，进一步表明了体内平衡的生理作用。
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, 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, 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.