The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor

Tracy Tzu Ling Tang, Donald Dowbenko, Amanda Jackson, Lisa Toney, David A. Lewin, Alexander Dent, Laurence A. Lasky

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

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 ∼4-7-fold. An examination of the BCL-6 promoter demonstrated that AFX bound to specific target sites that could activate transcription. BCL-XL, an anti-apoptotic protein, contains potential BCL-6 target sites in its promoter. An analysis of endogenous BCL-XL levels in AFX-expressing cells revealed enhanced down-regulation of the transcript (∼1.3-1.7-fold) and protein, and BCL-6 directly binds to and suppresses the BCL-XL 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.

Original languageEnglish
Pages (from-to)14255-14265
Number of pages11
JournalJournal of Biological Chemistry
Volume277
Issue number16
DOIs
StatePublished - Apr 19 2002

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Forkhead Transcription Factors
PTEN Phosphohydrolase
Apoptosis
Proto-Oncogene Proteins c-akt
Apoptosis Regulatory Proteins
Macrophages
Transcription
Phosphoric Monoester Hydrolases
Tumors
Phosphotransferases
Down-Regulation
Genes
Chemical activation
Lipids
Mutation
Neoplasms
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry

Cite this

The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. / Tang, Tracy Tzu Ling; Dowbenko, Donald; Jackson, Amanda; Toney, Lisa; Lewin, David A.; Dent, Alexander; Lasky, Laurence A.

In: Journal of Biological Chemistry, Vol. 277, No. 16, 19.04.2002, p. 14255-14265.

Research output: Contribution to journalArticle

Tang, Tracy Tzu Ling ; Dowbenko, Donald ; Jackson, Amanda ; Toney, Lisa ; Lewin, David A. ; Dent, Alexander ; Lasky, Laurence A. / The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 16. pp. 14255-14265.
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