Title | Noxa mediates p18INK4c cell-cycle control of homeostasis in B cells and plasma cell precursors. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Bretz J, Garcia J, Huang X, Kang L, Zhang Y, Toellner K-M, Chen-Kiang S |
Journal | Blood |
Volume | 117 |
Issue | 7 |
Pagination | 2179-88 |
Date Published | 2011 Feb 17 |
ISSN | 1528-0020 |
Keywords | Animals, Apoptosis, B-Lymphocytes, bcl-X Protein, Cell Cycle, Cell Differentiation, Cyclin-Dependent Kinase Inhibitor p18, HEK293 Cells, Hematopoietic Stem Cells, Homeostasis, Humans, Immunoglobulin G, Leukocyte Common Antigens, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Models, Biological, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-bcl-6, RNA, Small Interfering, Syndecan-1, Transcription Factors |
Abstract | 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(hi)/B220(hi) 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. Expression 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 G₁ arrest by p18 bypasses a homeostatic cell-cycle checkpoint in iPCs for PC differentiation. |
DOI | 10.1182/blood-2010-06-288027 |
Alternate Journal | Blood |
PubMed ID | 21163929 |
PubMed Central ID | PMC3062327 |
Grant List | R01 AR049436 / AR / NIAMS NIH HHS / United States R01 CA120531 / CA / NCI NIH HHS / United States T32-CA120531 / CA / NCI NIH HHS / United States T32-AR 49436 / AR / NIAMS NIH HHS / United States |
Related Faculty:
Selina Chen-Kiang, Ph.D.