BAX and BAK mediate p53-independent suppression of tumorigenesis.
BAX and BAK are essential regulators of proapoptotic signaling, and the disruption of apoptosis is linked to the development of cancer. To investigate the role of BAX and BAK in tumorigenesis, primary baby mouse kidney epithelial cells (BMKs) from wild-type, BAX-, BAK-, or BAK- and BAK-deficient mice were transformed by adenovirus E1A and dominant-negative p53 (p53DD). In wild-type BMKs, the expression of E1A and inactivation of p53 was sufficient for transformation but not tumorigenesis. In contrast, E1A- and p53DD-transformed BAX- and BAK-deficient BMKs formed highly invasive carcinomas. Transformed BMKs deficient for either BAX or BAK were also tumorigenic, but only when heterozygous for the remaining bax or bak allele, the expression of which was lost in most resulting tumors. Thus, BAX and BAK function to suppress tumorigenesis, and their deficiency was selected for in vivo.
Degenhardt
Kurt
K
Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers University, 679 Hoes Lane, Room 140, Piscataway, NJ 08854, USA.
Chen
Guanghua
G
Lindsten
Tullia
T
White
Eileen
E
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics*; D007668:Kidney / Q000502:physiology; D019656:Loss of Heterozygosity; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014183:Transplantation, Heterologous; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein