Steroid- and retinoid-mediated growth arrest and apoptosis in WEHI-231 cells: role of NF-kappaB, c-Myc and CKI p27(Kip1).
IgM cross-linking induces NF-kappaB inactivation, c-Myc down-regulation, and cyclin kinase inhibitor p27(Kip1) accumulation in WEHI-231 murine B lymphoma cells. p27(Kip1) up-regulation leads to a decreased cyclin-dependent kinase 2 activity, retinoblastoma protein hypophosphorylation, G1 arrest and apoptosis. Similar to membrane (m) IgM cross-linking in B lymphoma cells, steroids and retinoids down-regulate c-Myc (via NF-kappaB inactivation) and induce apoptosis in T cell hybridomas and thymocytes. In this study, we determined if steroids and retinoids have similar effects in WEHI-231 cells. Our results show that steroids and retinoids induce NF-kappaB inactivation, c-Myc down-regulation, p27(Kip1) up-regulation, G1 arrest, and apoptosis. Importantly, these hormones enhance anti-IgM-induced apoptosis in WEHI-231 cells. Similar to mIgM signaling, all these effects are prevented by treatment with CD40 ligand. Caspase inhibition, on the other hand, rescues cells from steroid/retinoid-induced apoptosis, but has no effect on growth arrest, p27(Kip1), and c-Myc. Together, these findings suggest that steroids/retinoids and mIgM cross-linking share a common signal transduction pathway leading to G1 arrest and cell death.
Donjerković
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Department of Immunology, Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville 20855, USA.
Mueller
C M
CM
Scott
D W
DW
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D007075:Immunoglobulin M / Q000276:immunology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011940:Receptor Aggregation / Q000187:drug effects; D012176:Retinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000187:drug effects
D000590:Amino Acid Chloromethyl Ketones; D000888:Antibodies, Anti-Idiotypic; D061945:Caspase Inhibitors; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D012176:Retinoids; D013256:Steroids; D025521:Tumor Suppressor Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D023201:CD40 Ligand; D050760:Cyclin-Dependent Kinase Inhibitor p27; C055348:muristerone A; D004441:Ecdysterone; D003907:Dexamethasone; D020169:Caspases