The role of MAPKs in B cell receptor-induced down-regulation of Egr-1 in immature B lymphoma cells.
Cross-linking of the B cell receptor (BCR) on the immature B lymphoma cell line BKS-2 induces growth inhibition and apoptosis accompanied by rapid down-regulation of the immediate-early gene egr-1. In these lymphoma cells, egr-1 is expressed constitutively and has a prosurvival role, as Egr-1-specific antisense oligonucleotides or expression of a dominant-negative inhibitor of Egr-1 also prevented the growth of BKS-2 cells. Moreover, enhancement of Egr-1 protein with phorbol 12-myristate 13-acetate or an egr-1 expression vector rescued BKS-2 cells from BCR signal-induced growth inhibition. Nuclear run-on and mRNA stability assays indicated that BCR-derived signals act at the transcriptional level to reduce egr-1 expression. Inhibitors of ERK and JNK (but not of p38 MAPK) reduced egr-1 expression at the protein level. Transcriptional regulation appears to have a role because egr-1 promoter-driven luciferase expression was reduced by ERK and JNK inhibitors. Promoter truncation experiments suggested that several serum response elements are required for MAPK-mediated egr-1 expression. Our study suggests that BCR signals reduce egr-1 expression by inhibiting activation of ERK and JNK. Unlike ERK and JNK, p38 MAPK reduces constitutive expression of egr-1. Unlike the immature B lymphoma cells, normal immature B cells did not exhibit constitutive MAPK activation. BCR-induced MAPK activation was modest and transient with a small increase in egr-1 expression in normal immature B cells consistent with their inability to proliferate in response to BCR cross-linking.
Ke
Jiyuan
J
Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, Kentucky 40536, USA.
Gururajan
Murali
M
Kumar
Anupam
A
Simmons
Alan
A
Turcios
Lilia
L
Chelvarajan
Ralph L
RL
Cohen
David M
DM
Wiest
David L
DL
Monroe
John G
JG
Bondada
Subbarao
S
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D012190:Retroviridae / Q000502:physiology; D025721:WT1 Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006131:Growth Inhibitors; D016376:Oligonucleotides, Antisense; D011947:Receptors, Antigen, B-Cell; D025721:WT1 Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases