Role of c-myc and p27 in anti-IgM induced B-lymphoma apoptosis.
Crosslinking membrane IgM receptors on a set of murine B cell lymphomas leads to a rapid increase in c-myc, followed by a decrease in its expression to undetectable levels by 8-24 hours. These cells die soon thereafter via apoptosis. IgD receptor crosslinking also leads to an increase in c-myc expression, but it remains above baseline levels for more than 24 hours; these cells continue to proliferate and do not die. We previously reported that antisense oligonucleotides for c-myc prevented growth arrest and cell death in these lymphomas, independent of the presence of mitogenic CpG motifs. Indeed, antisense for c-myc actually led to a stabilization of c-myc message and protein. Growth arrest in these cells is dependent on the increased synthesis of the p27 cyclin kinase inhibitor (Kip1) normally induced after anti-IgM crosslinking. Consistent with its biologic effects, anti-IgD does not cause an increase in p27. Since dexamethasone causes a loss of myc and synergizes with the anti-IgM signal, we suggest that accelerated cell death with this steroid in the presence of anti-IgM is due to a more rapid degradation of this oncogene product. Finally, we propose that c-myc drives the transcription or activation of an inhibitor of the p27 Kip (Kipi). Hence, loss of c-myc in response to anti-IgM signals in these B-cell lymphomas leads to upregulation of p27, growth arrest and apoptosis. It follows that maintenance of c-myc in these B-cell lymphomas should lead to survival and no increase in p27.
Scott
D W
DW
Department of Immunology, Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, MD 20855, USA.
Donjerković
D
D
Maddox
B
B
Ezhevsky
S
S
Grdina
T
T
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000378:metabolism; D016259:Genes, myc; D007075:Immunoglobulin M / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008954:Models, Biological; D025521:Tumor Suppressor Proteins
D000888:Antibodies, Anti-Idiotypic; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D007075:Immunoglobulin M; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases