c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells

AbstractSeveral 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. (Blood. 2005;106:1382-1391)

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The role of bcl-xL in CD40-mediated rescue from anti-μ-induced apoptosis in WEHI-231 B lymphoma cells

European Journal of Immunology ◽

10.1002/eji.1830250533 ◽

1995 ◽

Vol 25 (5) ◽

pp. 1352-1357 ◽

Cited By ~ 113

Author(s):

Michael S. K. Choi ◽

Lawrence H. Boise ◽

Alexander R. Gottschalk ◽

José Quintans ◽

Craig B. Thompson ◽

...

Keyword(s):

Lymphoma Cells ◽

B Lymphoma ◽

B Lymphoma Cells ◽

Wehi 231 ◽

Induced Apoptosis

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Roles of the Tumor Suppressor p53 and the Cyclin-dependent Kinase Inhibitor p21WAF1/CIP1 in Receptor-mediated Apoptosis of WEHI 231 B Lymphoma Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.10.1671 ◽

1998 ◽

Vol 187 (10) ◽

pp. 1671-1679 ◽

Cited By ~ 35

Author(s):

Min Wu ◽

Robert E. Bellas ◽

Jian Shen ◽

Gail E. Sonenshein

Keyword(s):

Tumor Suppressor ◽

B Cell ◽

Kinase Inhibitor ◽

Ectopic Expression ◽

Cyclin Dependent Kinase ◽

Lymphoma Cells ◽

B Lymphoma ◽

Cyclin Dependent Kinase Inhibitor ◽

B Lymphoma Cells ◽

Wehi 231

Treatment of WEHI 231 immature B lymphoma cells with an antibody against their surface immunoglobulin M (anti-IgM) induces apoptosis and has been studied extensively as a model of self-induced B cell tolerance. Since the tumor suppressor protein p53 has been implicated in apoptosis in a large number of cell types and has been found to be mutated in a variety of B cell tumors, here we sought to determine whether p53 and the p53 target gene cyclin-dependent kinase inhibitor p21WAF1/CIP1 were involved in anti-IgM–induced cell death. Anti-IgM treatment of WEHI 231 cells increased expression of p53 and p21 protein levels. Ectopic expression of wild-type p53 in WEHI 231 cells induced both p21 expression and apoptosis. Ectopic expression of p21 similarly induced apoptosis. Rescue of WEHI 231 cells from apoptosis by costimulation with CD40 ligand ablated the increase in p21 expression. Lastly, a significant decrease in anti-IgM–mediated apoptosis was seen upon downregulation of endogenous p53 activity by expression of a dominant-negative p53 protein or upon microinjection of an antisense p21 expression vector or antibody. Taken together, the above data demonstrate important roles for p53 and p21 proteins in receptor-mediated apoptosis of WEHI 231 B cells.

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