CD40 and B-cell receptor signalling induce MAPK family members that can either induce or repress Bcl-6 expression.
Bcl-6 is essential for germinal centre development and normal antibody responses, and has major roles in controlling B-cell proliferation and differentiation. Bcl-6 expression is tightly controlled, but neither the nature of all the regulatory signals nor their interactions are known. Bcl-6 expression is induced in Bcr-Abl expressing lymphoid cell lines by the tyrosine kinase inhibitor, imatinib. We show that p38 MAPK mediates induction of Bcl-6 following inhibition of Bcr-Abl by imatinib. Next we analyze p38 function in a germinal centre B-cell line, Ramos. p38 is phosphorylated under basal conditions, and studies with p38 inhibitors show that it induces Bcl-6 expression. Membrane bound CD40 ligand activates p38 but also other MAPK pathways that strongly repress Bcl-6 and the overall effect is reduction in Bcl-6 expression. Surprisingly soluble CD40 ligand induces Bcl-6 by activating p38 without activating the repressive pathways. Hence different types of CD40 signalling are associated with varying effects on Bcl-6 expression. Transcription reporter assays demonstrate p38 responsive sequences at about 4.5 kb from the transcription start site. Immunocytochemistry of tonsil sections show phosphorylated p38 in a minor population of germinal centre B-cells. We demonstrate for the first time that p38 induces Bcl-6 transcription, but increased protein expression occurs only when the strong pathways repressing Bcl-6 are not activated.
Batlle
Ana
A
Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Papadopoulou
Vasiliki
V
Gomes
Ana R
AR
Willimott
Shaun
S
Melo
Junia V
JV
Naresh
Kikkeri
K
Lam
Eric W-F
EW
Wagner
Simon D
SD
D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism; D019013:CD40 Antigens / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology; D008954:Models, Biological; D014066:Palatine Tonsil / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D051560:Proto-Oncogene Proteins c-bcl-6; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D016044:Fusion Proteins, bcr-abl; D048049:Extracellular Signal-Regulated MAP Kinases