c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells.
Several primary murine and human B lymphomas and cell lines were found to constitutively express high levels of the activated form of c-jun N-terminal kinase (JNK), a member of the mitogen-activated protein (MAP) kinase family. Proliferation of murine B lymphomas CH31, CH12.Lx, BKS-2, and WEHI-231 and the human B lymphomas BJAB, RAMOS, RAJI, OCI-Ly7, and OCI-Ly10 was strongly inhibited by SP600125, an anthrapyrazolone inhibitor of JNK, in a dose-dependent manner. The lymphoma cells underwent apoptosis and arrested at the G2/M phase of cell cycle. Furthermore, JNK-specific small interfering RNA (siRNA) inhibited the growth of both murine and human B lymphomas. Thus in the B-lymphoma model, JNK appears to have a unique prosurvival role. Survival signals provided by CD40 and interleukin-10 (IL-10) together reversed the growth inhibition induced by the JNK inhibitor. c-Myc protein levels were reduced in the presence of both SP600125 and JNK-specific siRNA, and CD40 ligation restored c-Myc levels. Moreover, Bcl-xL rescued WEHI-231 cells from apoptosis induced by the JNK inhibitor. The JNK inhibitor also reduced levels of early growth response gene-1 (Egr-1) protein, and overexpressing Egr-1 partially rescued lymphoma cells from apoptosis. Thus, JNK may act via c-Myc and Egr-1, which were shown to be important for B-lymphoma survival and growth.
Gururajan
Murali
M
Department of Microbiology, Immunology, & Molecular Genetics, University of Kentucky, Lexington, KY, USA.
Chui
Roger
R
Karuppannan
Anbu K
AK
Ke
Jiyuan
J
Jennings
C Darrell
CD
Bondada
Subbarao
S
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc; D047069:Pyrazolones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D016271:Proto-Oncogene Proteins c-myc; D047069:Pyrazolones; D034741:RNA, Small Interfering; D014157:Transcription Factors; C050637:losoxantrone; D048031:JNK Mitogen-Activated Protein Kinases