CD40 signaling in B cells regulates the expression of the Pim-1 kinase via the NF-kappa B pathway.
The ability of CD40 signaling to regulate B cell growth, survival, differentiation, and Ig class switching involves many changes in gene expression. Using cDNA expression arrays and Northern blotting, we found that CD40 signaling increased the mRNA levels for pim-1, a protooncogene that encodes a serine/threonine protein kinase. Subsequent experiments showed that CD40 engagement also increased both Pim-1 protein levels and Pim-1 kinase activity in B cells. We then investigated the signaling pathways by which CD40 regulates Pim-1 expression and found that CD40 up-regulates Pim-1 primarily via the activation of NF-kappaB. Inhibiting the activation of NF-kappaB, either by treating cells with a chemical inhibitor, BAY11-7082, or by inducibly expressing a superrepressor form of IkappaBalpha, significantly impaired the ability of CD40 to increase Pim-1 protein levels. Because Pim-1 expression is associated with cell proliferation and survival, we asked whether this correlated with the ability of CD40 signaling to prevent anti-IgM-induced growth arrest in the WEHI-231 murine B cell line, a model for Ag-induced clonal deletion. We found that the anti-IgM-induced growth arrest in WEHI-231 cells correlated with a substantial decrease in Pim-1 levels. In contrast, culturing WEHI-231 cells with either anti-CD40 Abs or with the B cell mitogen LPS, both of which prevent the anti-IgM-induced growth arrest, also prevented the rapid decline in Pim-1 levels. This suggests that Pim-1 could regulate the survival and proliferation of B cells.
Zhu
Nongliao
N
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Ramirez
Luis M
LM
Lee
Rosaline L
RL
Magnuson
Nancy S
NS
Bishop
Gail A
GA
Gold
Michael R
MR
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D019013:CD40 Antigens; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1