Noxa mediates p18INK4c cell-cycle control of homeostasis in B cells and plasma cell precursors
Noxa mediates p18INK4c cell-cycle control of homeostasis in B cells and plasma cell precursors
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DOI：
10.1182/blood-2010-06-288027
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发表时间：
2011-02-17
期刊：
影响因子：
20.3
通讯作者：
Chen-Kiang, Selina
中科院分区：
文献类型：
--
作者：
Bretz, Jamieson;Garcia, Josefina;Chen-Kiang, Selina
p18(INK4c) (p18) 对 Cdk4/Cdk6 的抑制对于非循环免疫球蛋白 (Ig) 分泌浆细胞 (PC) 的生成至关重要。在缺乏p18的情况下，CD138(+)浆细胞样细胞继续快速循环和周转，表明p18控制PC稳态。我们现在表明，p18 选择性地作用于罕见的快速循环 CD138(hl)/B220(hl) 中间 PC (iPC) 群体。在保留某些 B 细胞特征的同时，iPC 仍准备分化为终末期 PC，尽管大多数会发生凋亡。 p18 对于 PC 转录电路的发育是不可或缺的，并且 Blimp-1 和 Bcl-6 在各个 iPC 中完全且相互排斥地表达。然而，一小部分 iPC 两者都表达，并且它们优先受到 p18 或 Bcl-xL 过表达的保护，这与 Bcl-xL 过表达或促凋亡 Bim 或 Noxa 丧失导致的 iPC 池扩展一致。 Noxa 的表达在 B 细胞激活过程中被诱导，在 iPC 中达到峰值，并被 p18 选择性抑制。它是促进循环 B 细胞凋亡所必需的，尤其是在缺乏 p18 的情况下。这些发现定义了 Noxa 的第一个生理功能，并表明通过抑制 Noxa，p18 诱导的 G(1) 阻滞绕过了 iPC 中用于 PC 分化的稳态细胞周期检查点。 （血。2011；117(7):2179-2188）
Inhibition of Cdk4/Cdk6 by p18(INK4c) (p18) is pivotal for generation of noncycling immunoglobulin (Ig)-secreting plasma cells (PCs). In the absence of p18, CD138(+) plasmacytoid cells continue to cycle and turnover rapidly, suggesting that p18 controls PC homeostasis. We now show that p18 selectively acts in a rare population of rapidly cycling CD138(hl)/B220(hl) intermediate PCs (iPCs). While retaining certain B-cell signatures, iPCs are poised to differentiate to end-stage PCs although the majority undergo apoptosis. p18 is dispensable for the development of the PC transcriptional circuitry, and Blimp-1 and Bcl-6 are expressed fully and mutually exclusively in individual iPCs. However, a minor proportion of iPCs express both, and they are preferentially protected by p18 or Bcl-xL overexpression, consistent with expansion of the iPC pool by Bcl-xL overexpression, or loss of proapoptotic Bim or Noxa. Expres- sion of Noxa is induced during B-cell activation, peaks in iPCs, and selectively repressed by p18. It is required to promote apoptosis of cycling B cells, especially in the absence of p18. These findings define the first physiologic function for Noxa and suggest that by repressing Noxa, induction of G(1) arrest by p18 bypasses a homeostatic cell-cycle checkpoint in iPCs for PC differentiation. (Blood. 2011;117(7):2179-2188)