Dysregulated bcl-2 expression inhibits apoptosis but not differentiation of retinoic acid-induced HL-60 granulocytes.
The bcl-2-proto-oncogene appears to contribute to the development of certain malignancies by inhibiting programmed cell death (apoptosis). Mature granulocytes show a markedly limited life span and rapidly undergo apoptosis. To further define the relationship between apoptosis and granulocyte differentiation, we used retroviral vector-mediated gene transduction to introduce the normal bcl-2 gene into the HL-60 myeloid leukemia cell line and determined the response of these bcl-2-transduced HL-60 cells to the induction of granulocyte differentiation by retinoic acid (RA). Although the bcl-2-transduced HL-60 cells showed the same differentiative response to RA as did the parental HL-60 cells, the life span of the RA-induced, bcl-2-transduced HL-60 granulocytes was markedly prolonged compared with that of the RA-induced parental HL-60 granulocytes. DNA fragmentation studies indicate that this prolonged life span resulted from diminished apoptosis in the bcl-2-transduced cells. These studies indicate that bcl-2 is involved in regulating apoptosis in maturing granulocytes. Because bcl-2 over-expression did not interfere with RA-induced granulocyte differentiation, it appears that granulocyte differentiation and apoptosis are under distinct and separate regulatory controls.
Program in Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
J R
JR
Park
K
K
Robertson
D D
DD
Hickstein
S
S
Tsai
D M
DM
Hockenbery
S J
SJ
Collins
D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D004249:DNA Damage; D015973:Gene Expression Regulation, Leukemic; D006098:Granulocytes / Q000166:cytology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014212:Tretinoin