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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / physiology
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B-Lymphocytes / cytology*
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B-Lymphocytes / physiology*
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Cyclin-Dependent Kinase Inhibitor p18 / deficiency
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Cyclin-Dependent Kinase Inhibitor p18 / genetics
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Cyclin-Dependent Kinase Inhibitor p18 / physiology*
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HEK293 Cells
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / physiology
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Homeostasis / genetics
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Homeostasis / physiology
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Humans
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Immunoglobulin G / biosynthesis
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Leukocyte Common Antigens / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Models, Biological
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Plasma Cells / cytology*
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Plasma Cells / physiology*
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Positive Regulatory Domain I-Binding Factor 1
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / deficiency
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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Proto-Oncogene Proteins c-bcl-6 / genetics
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Proto-Oncogene Proteins c-bcl-6 / physiology
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RNA, Small Interfering / genetics
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Syndecan-1 / metabolism
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Transcription Factors / genetics
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Transcription Factors / physiology
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bcl-X Protein / genetics
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bcl-X Protein / physiology
Substances
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Bcl2l1 protein, mouse
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Cdkn2c protein, mouse
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Cyclin-Dependent Kinase Inhibitor p18
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Immunoglobulin G
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PMAIP1 protein, human
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Pmaip1 protein, mouse
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Prdm1 protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-bcl-6
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RNA, Small Interfering
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Sdc1 protein, mouse
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Syndecan-1
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Transcription Factors
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bcl-X Protein
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Positive Regulatory Domain I-Binding Factor 1
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Leukocyte Common Antigens