Role of bcl-X(L) in the control of apoptosis in murine myeloma cells.
The development of an increasing number of tumors has been shown to involve the deregulation of not only cell proliferation but also normal cell death by apoptosis. Expression of the bcl-2 proto-oncogene has been shown to inhibit the apoptotic cell death of many types of cells. Recent work also has revealed the existence of several bcl-2-related genes that also can inhibit (e.g., bcl-X(L) and Mcl-1) or activate (e.g., bax, bcl-X(s), bag, and bad) apoptosis in several systems. Myelomas are antibody-secreting tumor cells derived from terminally differentiated B lymphocytes, and previous work from our laboratory showed that murine SP2/0 myeloma cells and derived B-cell hybridomas were highly sensitive to apoptosis induction by a block of gene expression (cycloheximide). Additional work revealed that a related murine myeloma cell line, P3X63Ag8.653, was resistant to apoptosis induction in similar conditions. To understand the genetic basis of this differential susceptibility, we examined the expression of apoptosis-related genes in these cell lines. Northern blot experiments showed no significant difference in the expression of myc and bax apoptosis-promoting genes in susceptible (SP2/0 and D5) and resistant (P3X63) cell lines. Also, no significant expression of the bcl-2 gene could be detected in these cell lines. However, a much higher expression level of bcl-X(L) mRNA was observed in apoptosis-resistant P3X63Ag8.653 cells. The role of bcl-X(L) was supported by the finding that expression of bcl-X(L) cDNA in transfected, apoptosis-sensitive D5 cells increased the viability of these cells greatly and reduced DNA fragmentation following apoptosis induction. Significant bcl-X(L) but not bcl-2 expression was also detected in three other murine myeloma cell lines (MOPC 315, RPC 5.4, and J558) derived from different plasmacytoma tumors. These results indicate a predominant role of bcl-X(L) in preventing apoptosis in myeloma cells and suggest that the expression of bcl-2 or bcl-X(L) genes in B-cell tumors depends on the differentiation stage of the precursor normal cell.
Gauthier
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Canadian Red Cross Blood Transfusion Service, Quebec, Canada.
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Lemieux
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Lemieux
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D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D003513:Cycloheximide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006825:Hybridomas; D051379:Mice; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010954:Plasmacytoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003513:Cycloheximide