Life and death decisions in B1 lymphoma cells.
Crosslinking of surface immunoglobulin (Ig) receptors with anti-IgM (anti-mu) but not anti-IgD (anti-delta) antibodies causes growth arrest and apoptosis in several extensively characterized B1-like lymphoma cell lines. While anti-mu stimulates a transient increase in c-myc mRNA and protein expression, followed by a rapid decline below the baseline level, anti-delta only causes a moderate increase in the expression of this oncogene, which returns to baseline levels within 24-48 hours. However, signals downstream from anti-delta can be converted into an apoptotic pathway by modulating PI3K activity, suggesting that PI3K is a critical rheostat controlling survival signals in B1 cell lines. Anti-mu-induced down-regulation of c-Myc is followed in time with an increase in the cyclin dependent kinase inhibitor, p27Kip1, in all anti-mu sensitive lymphoma lines. This increase correlates with growth arrest and apoptosis. The anti-mu-mediated decrease in c-Myc, increase in p27Kip1, growth arrest and apoptosis, can all be prevented via CD40/CD40L signaling. Inhibition of caspase activation, on the other hand, prevents anti-mu-induced apoptosis, but has no effect on c-Myc, p27Kip1, and G1 arrest. Interestingly, we also found that steroids and retinoids can mimic anti-mu-mediated signaling and lead to a loss of c-Myc, an increase in p27Kip1, G1 arrest, and apoptosis. Together, these data suggest that modulation of c-Myc and p27Kip1 protein levels is crucial for the life versus death decisions in murine immature B1-like lymphoma cells lines.
Donjerković
D
D
Department of Immunology, American Red Cross Holland Laboratory, Rockville, MD 20855, USA.
Carey
G B
GB
Mueller
C M
CM
Liu
S
S
Scott
D W
DW
D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000502:physiology; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone / Q000494:pharmacology; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004792:Enzyme Precursors / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016393:Lymphoma, B-Cell / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D018797:Cell Cycle Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C039951:anti-IgD; C044203:anti-IgM; D023201:CD40 Ligand; D050760:Cyclin-Dependent Kinase Inhibitor p27; C055348:muristerone A; D004441:Ecdysterone; D014212:Tretinoin; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D020169:Caspases