Molecular mechanisms associated with the regulation of apoptosis by the two alternatively spliced products of c-Myb.
The c-myb proto-oncogene encodes two alternatively spliced mRNAs, which in turn code for proteins of 75 kDa and 89 kDa. It is at present unclear whether the two isoforms of c-Myb perform identical functions or whether they mediate different biological effects. To assess their role in apoptotic death of hematopoietic cells, we expressed the two isoforms of c-Myb in the murine myeloid cell lines 32Dcl3 and FDCP1. Our results show that while ectopic overexpression of p75 c-Myb results in the acceleration of cell death, similar overexpression of p89 c-Myb results in the protection of cells from apoptotic death. An analysis of gene expression changes with mouse cDNA expression arrays revealed that while p75 c-Myb blocked the expression of glutathione S-transferase micro mRNA, p89 c-Myb greatly enhanced the expression of this gene. These results were further confirmed by Northern blot analysis. Ectopic overexpression of the glutathione S-transferase micro gene in 32Dcl3 cells resulted in protection of cells from interleukin-3 withdrawal-induced cell death similar to that seen with the ectopic overexpression of p89 c-Myb. These results suggest that the two isoforms of c-Myb differentially regulate apoptotic death of myeloid cells through differential regulation of glutathione S-transferase micro gene expression.
Kumar
Atul
A
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, PA 19140, USA.
Baker
Stacey J
SJ
Lee
Clement M
CM
Reddy
E Premkumar
EP
D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001854:Bone Marrow Cells / Q000473:pathology / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D022423:Myeloid Cells / Q000473:pathology / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation
D003574:Cytochrome c Group; D007377:Interleukin-3; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D020598:Proto-Oncogene Proteins c-myb; D005982:Glutathione Transferase; D020169:Caspases