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

Tracy Tzu-Ling Tang1, Donald Dowbenko, Amanda Jackson

  • 1Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.

The Journal of Biological Chemistry
|January 5, 2002
PubMed

Insights

Forkhead transcription factor AFX triggers apoptosis by up-regulating BCL-6, a repressor that suppresses anti-apoptotic BCL-XL. This pathway contributes to tumor survival and apoptotic resistance.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Mutations in PTEN activate AKT/protein kinase B, promoting tumor cell survival by inhibiting apoptosis.
  • Forkhead transcription factors, including AFX, are involved in regulating apoptosis and can be inhibited by AKT signaling.

Purpose of the Study:

  • To elucidate the AFX-regulated pathway involved in apoptosis.
  • To investigate the role of AFX in regulating the expression of apoptosis-related genes, specifically BCL-6 and BCL-XL.

Main Methods:

  • Analysis of gene expression in AFX-expressing cells.
  • Chromatin immunoprecipitation assays to determine transcription factor binding.
  • Reporter assays to assess transcriptional activation/repression.
  • Western blotting and quantitative PCR to measure protein and transcript levels.
  • Macrophage survival assays in BCL-6 knockout mice.

Main Results:

  • AFX expression induces apoptosis and up-regulates the transcriptional repressor BCL-6.
  • AFX directly binds to and activates the BCL-6 promoter.
  • BCL-6 represses the expression of the anti-apoptotic protein BCL-XL.
  • Macrophages from BCL-6 knockout mice exhibit enhanced survival.

Conclusions:

  • AFX regulates apoptosis partly by suppressing BCL-XL levels via BCL-6.
  • This AFX-BCL-6-BCL-XL axis represents a novel mechanism in apoptotic regulation within tumors.

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