ROLES OF THE TUMOR-SUPPRESSOR P53 AND THE CYCLIN-DEPENDENT KINASE INHIBITOR P21(WAF1 CTP1) IN RECEPTOR-MEDIATED APOPTOSIS OF WEHI-231 B-LYMPHOMA-CELLS/

Treatment of WEHI 231 immature B lymphoma cells with an antibody again st 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 apoptos is in a large number of cell types and has been found to be mutated in a variety of B cell tumors, hers we sought to determine whether p53 a nd the p53 target gene cyclin-dependent kinase inhibitor p21(WAF1/CIP1 ) were involved in anti-IgM-induced cell death. Anti-IgM treatment of WEHI 231 cells increased expression of p53 and p21 protein levels. Ect opic expression of wild-type p53 in WEHI 231 cells induced both p21 ex pression and apoptosis. Ectopic expression of p21 similarly induced ap optosis. Rescue of WEHI 231 cells from apoptosis by costimulation with CD40 ligand ablated the increase in p21 expression. Lastly, a signifi cant decrease in anti-IgM-mediated apoptosis was seen upon downregulat ion of endogenous p53 activity by expression of a dominant-negative p5 3 protein or upon microinjection of an antisense p21 expression vector or antibody. Taken together, the above data demonstrate important rol es for p53 and p21 proteins in receptor-mediated apoptosis of WEHI 231 B cells.