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Bacillus anthracis lethal toxin represses MMTV promoter activity through transcription factors

Zhigang Kang1, Jeanette I Webster Marketon, Antoinette Johnson

  • 1Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N13 (MSC 9401), Bethesda, MD 20892-9401, USA.

Journal of Molecular Biology
|April 25, 2009
PubMed

Insights

Anthrax lethal toxin (LeTx) targets key transcription factors, decreasing their protein levels and repressing gene activation. Early LeTx antagonist treatment can prevent these effects, revealing new molecular actions of the toxin.

Area of Science:

  • Molecular Biology
  • Toxicology
  • Cellular Biology

Background:

  • Anthrax lethal toxin (LeTx) is known to repress nuclear hormone receptors.
  • Understanding the molecular mechanisms of LeTx toxicity is crucial for developing effective countermeasures.

Purpose of the Study:

  • To investigate the effect of LeTx on specific transcription factors.
  • To determine the role of LeTx protease activity in transcription factor degradation.
  • To explore the potential of LeTx antagonists in mitigating toxin effects.

Main Methods:

  • Assessing LeTx effects on mouse mammary tumor virus promoter activity.
  • Quantifying protein levels of transcription factors (HNF-3, Oct-1, c-Jun) after LeTx exposure.
  • Evaluating the impact of LeTx antagonists on LeTx-induced repression.
  • Comparing the kinetics of transcription factor degradation with mitogen-activated protein kinase kinase cleavage.

Main Results:

  • LeTx repressed the activation of the mouse mammary tumor virus promoter, involving transcription factors HNF-3, Oct-1, and c-Jun.
  • LeTx reduced protein levels of these transcription factors in a manner dependent on lethal factor protease activity.
  • Early administration of LeTx antagonists effectively blocked LeTx-mediated repression.
  • Degradation of these transcription factors occurred later than the cleavage of MAP kinases by LeTx.

Conclusions:

  • Transcription factors are identified as intracellular targets of anthrax lethal toxin.
  • These findings elucidate later-stage molecular actions of LeTx, particularly at low doses.
  • The study highlights the potential of targeting transcription factor degradation pathways for therapeutic intervention.

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