TY - JOUR
T1 - Noxa mediates p18(INK4c) cell-cycle control of homeostasis in B cells and plasma cell precursors
AU - Bretz, J
AU - Garcia, J
AU - Huang, X
AU - Kang, L
AU - Zhang, Yang
AU - Toellner, Kai-Michael
AU - Chen-Kiang, S
PY - 2011/2/1
Y1 - 2011/2/1
N2 - 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)
AB - 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)
U2 - 10.1182/blood-2010-06-288027
DO - 10.1182/blood-2010-06-288027
M3 - Article
C2 - 21163929
SN - 1528-0020
VL - 117
SP - 2179
EP - 2188
JO - Blood
JF - Blood
IS - 7
ER -