Role of Mtd/Bok in normal and neoplastic B-cell development in the bursa of Fabricius.
B-cell development in the bursa of Fabricius is accompanied by extensive apoptotic cell death. Apoptosis, however, is suppressed during c-myc-induced neoplasia. The experiments described here suggest that Mtd/Bok may drive apoptosis during normal development, and that this activity is blocked during myc-induced tumorigenesis. Bursal Mtd/Bok expression increases during development, correlating with the onset of intense, spontaneous apoptosis after hatching. Two isoforms of Mtd/Bok were characterized: WT-chMtd/Bok, found predominantly in the mitochondria and a less abundant form, lacking the presumptive transmembrane domain, Mtd/Bok deltaTM, found predominantly in the cytosol. Over-expression of Mtd/Bok deltaTM in a bursal lymphoma-derived cell line, DT40, reduced mitochondrial function and sensitized DT40 cells to apoptotic stimuli, while WT-chMtd/Bok had a diminished phenotype in these cells. In contrast, retroviral transduction of bursal stem cells with WT-chMtd/Bok ablated normal stem cell function in transplantation experiments, and produced extensive apoptosis in myc-induced pre-neoplastic bursal populations, but not in tumor cells.
Brown
Cheryl Y
CY
Fred Hutchinson Cancer Research Center, Divisions of Basic Science and Human Biology, 1100 Fairview Avenue N., C2-023, P.O. Box 19024, Seattle, WA 9819-1024, USA.
Bowers
Sandra J
SJ
Loring
Gibert
G
Heberden
Christine
C
Lee
Ruey-Min
RM
Neiman
Paul E
PE
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002060:Bursa of Fabricius / Q000196:embryology / Q000276:immunology*; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology*; D002642:Chick Embryo / Q000196:embryology / Q000276:immunology*; D015151:Immunoblotting / Q000662:veterinary; D016393:Lymphoma, B-Cell / Q000196:embryology / Q000276:immunology / Q000473:pathology*; D008928:Mitochondria / Q000276:immunology; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D012313:RNA / Q000097:blood / Q000235:genetics; D016415:Sequence Alignment; D014162:Transfection / Q000662:veterinary
D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D012313:RNA