Increased p27Kip1 cyclin-dependent kinase inhibitor gene expression following anti-IgM treatment promotes apoptosis of WEHI 231 B cells.
Engagement of the B cell receptor of WEHI 231 immature B cells leads sequentially to a drop in c-Myc, to induction of the cyclin-dependent kinase inhibitor p27Kip1, and finally to apoptosis. Recently we demonstrated that the drop in c-Myc expression promotes cell death, whereas the induction of p27 has been shown to lead to growth arrest. In this paper, we demonstrate that increased p27 expression also promotes apoptosis of WEHI 231 B cells. The rescue of WEHI 231 cells by CD40 ligand engagement of its receptor prevented the increase in p27 induction. Inhibition of p27-ablated apoptosis induced upon expression of antisense c-myc RNA. Furthermore, specific induction of p27 gene expression resulted in apoptosis of WEHI 231 cells. Lastly, inhibition of expression of c-Myc, upon induction of an antisense c-myc RNA vector, was sufficient to induce increased p27 levels and apoptosis. Thus, these findings define a signaling pathway during B cell receptor engagement in which the drop in c-Myc levels leads to an increase in p27 levels that promotes apoptosis.
Wu
M
M
Department of Biochemistry, Boston University Medical School, MA 02118, USA.
Bellas
R E
RE
Shen
J
J
Yang
W
W
Sonenshein
G E
GE
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000096:biosynthesis / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D016372:RNA, Antisense / Q000096:biosynthesis / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins
D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D007075:Immunoglobulin M; D008024:Ligands; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D016372:RNA, Antisense; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C044203:anti-IgM; D023201:CD40 Ligand; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases