title: Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells.
abstract: Treatment of WEHI 231 immature B-lymphoma cells with an antibody against their surface immunoglobulin (anti-Ig) induces apoptosis and has been studied extensively as a model of B-cell tolerance. Anti-Ig treatment of exponentially growing WEHI 231 cells results in an early transient increase in c-myc expression that is followed by a decline to below basal levels; this decrease in c-myc expression immediately precedes the induction of cell death. Here we have modulated NF-kappaB/Rel factor activity, which regulates the rate of c-myc gene transcription, to determine whether the increase or decrease in c-Myc-levels mediates apoptosis in WEHI 231 cells. Addition of the serine/threonine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), which blocks the normally rapid turnover of the specific inhibitor of NF-kappaB/Rel IkappaBalpha in these cells, caused a drop in Rel-related factor binding. TPCK treatment resulted in decreased c-myc expression, preventing the usual increase seen following anti-Ig treatment. Whereas inhibition of the induction of c-myc expression mediated by anti-Ig failed to block apoptosis, reduction of c-myc expression in exponentially growing WEHI 231 cells induced apoptosis even in the absence of anti-Ig treatment. In WEHI 231 clones ectopically expressing c-Myc, apoptosis induced by treatment with TPCK or anti-Ig was significantly diminished and cells continued to proliferate. Furthermore, apoptosis of WEHI 231 cells ensued following enhanced expression of Mad1, which has been found to reduce functional c-Myc levels. These results indicate that the decline in c-myc expression resulting from the drop in NF-kappaB/Rel binding leads to activation of apoptosis of WEHI 231 B cells.
authors: Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
authors: M
authors: M
authors: Wu
authors: M
authors: M
authors: Arsura
authors: R E
authors: RE
authors: Bellas
authors: M J
authors: MJ
authors: FitzGerald
authors: H
authors: H
authors: Lee
authors: S L
authors: SL
authors: Schauer
authors: D H
authors: DH
authors: Sherr
authors: G E
authors: GE
authors: Sonenshein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003587:Cytomegalovirus / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C501385:Mad1l1 protein, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D020569:Proto-Oncogene Proteins c-rel; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014108:Tosylphenylalanyl Chloromethyl Ketone