title: Noxa mediates p18INK4c cell-cycle control of homeostasis in B cells and plasma cell precursors.
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.
authors.affiliation: Department of Pathology, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Jamieson
authors.initials: J
authors.lastname: Bretz
authors.forename: Josefina
authors.initials: J
authors.lastname: Garcia
authors.forename: Xiangao
authors.initials: X
authors.lastname: Huang
authors.forename: Lin
authors.initials: L
authors.lastname: Kang
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kai-Michael
authors.initials: KM
authors.lastname: Toellner
authors.forename: Selina
authors.initials: S
authors.lastname: Chen-Kiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D010950:Plasma Cells / Q000166:cytology* / Q000502:physiology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D053668:Syndecan-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D051020:bcl-X Protein / Q000235:genetics / Q000502:physiology
chemical_list: C494812:Bcl2l1 protein, mouse; C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; D007074:Immunoglobulin G; C498702:PMAIP1 protein, human; C408009:Pmaip1 protein, mouse; C513258:Prdm1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D034741:RNA, Small Interfering; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D014157:Transcription Factors; D051020:bcl-X Protein; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017493:Leukocyte Common Antigens