The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor.
The activation of the AKT/protein kinase B kinases by mutation of the PTEN lipid phosphatase results in enhanced survival of a diversity of tumors. This resistance to apoptosis is partly accomplished by the inhibition of genetic programs induced by a subfamily of forkhead transcription factors including AFX. Here we describe an AFX-regulated pathway that appears to account for at least part of this apoptotic regulatory system. Cells induced to synthesize an active form of AFX die by activating the apoptotic death pathway. An analysis of genes regulated by AFX demonstrated that BCL-6, a transcriptional repressor, is up-regulated approximately 4-7-fold. An examination of the BCL-6 promoter demonstrated that AFX bound to specific target sites that could activate transcription. BCL-X(L), an anti-apoptotic protein, contains potential BCL-6 target sites in its promoter. An analysis of endogenous BCL-X(L) levels in AFX-expressing cells revealed enhanced down-regulation of the transcript ( approximately 1.3-1.7-fold) and protein, and BCL-6 directly binds to and suppresses the BCL-X(L) promoter. Finally, macrophages isolated from BCL-6-/- mice show enhanced survival in vitro. These results suggest that AFX regulates apoptosis in part by suppressing the levels of anti-apoptotic BCL-XL through the transcriptional repressor BCL-6.
Tang
Tracy Tzu-Ling
TT
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
Dowbenko
Donald
D
Jackson
Amanda
A
Toney
Lisa
L
Lewin
David A
DA
Dent
Alexander L
AL
Lasky
Laurence A
LA
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors; D005821:Genetic Techniques; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C108803:FOXO4 protein, human; D051858:Forkhead Transcription Factors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D051020:bcl-X Protein; D004247:DNA; D008156:Luciferases