Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals.
BH3-only proteins function at a proximal point in a conserved cell death pathway by binding, through their BH3 domains, to other Bcl-2 family members and triggering mitochondrial events associated with apoptosis. Here, we describe a strongly pro-apoptotic BH3-only protein, designated Bbc3, whose expression increases in response to diverse apoptotic stimuli. bbc3 mRNA levels were induced by exposure to DNA-damaging agents and by wild-type p53, which mediates DNA damage-induced apoptosis. p53 transactivated bbc3 through consensus p53 binding sites within the bbc3 promoter region, indicating that bbc3 is a direct target of p53. Additionally, bbc3 mRNA was induced by p53-independent apoptotic stimuli, including dexamethasone treatment of thymocytes, and serum deprivation of tumor cells. Insulin-like growth factor-1 and epidermal growth factor, growth factors with broad anti-apoptotic activity, were each sufficient to suppress Bbc3 expression in serum-starved tumor cells. These results suggest that the transcriptional regulation of bbc3 contributes to the transduction of diverse cell death and survival signals.
Han
J
J
ImmunoGen, Inc., 128 Sidney Street, Cambridge, MA 02139, USA.
Flemington
C
C
Houghton
A B
AB
Gu
Z
Z
Zambetti
G P
GP
Lutz
R J
RJ
Zhu
L
L
Chittenden
T
T
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D001665:Binding Sites; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D016384:Consensus Sequence; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D007951:Leukemia, Myeloid; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53