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Oncoprotein suppression of tumor necrosis factor-induced NF kappa B activation is independent of Raf-controlled

Julie L Hanson1, Vasiliki Anest, Julie Reuther-Madrid

  • 1Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, 27599-7295, USA.

The Journal of Biological Chemistry
|July 10, 2003
PubMed

Insights

Oncoproteins like Ras and BCR-ABL block tumor necrosis factor (TNF)-induced activation of nuclear factor kappa B (NF kappa B) by inhibiting key signaling pathways. This interference affects NF kappa B-dependent gene expression, suggesting novel oncogenic mechanisms.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Oncology

Background:

  • Oncoproteins such as Ras and BCR-ABL are known to activate the transcription factor NF kappa B.
  • NF kappa B activity is crucial for cellular transformation mediated by these oncoproteins.
  • It is not fully understood if these oncoproteins modulate the entire NF kappa B signaling network or interfere with other stimuli.

Purpose of the Study:

  • To investigate whether Ras and BCR-ABL oncoproteins interfere with NF kappa B activation by other stimuli, specifically tumor necrosis factor (TNF).
  • To elucidate the specific mechanisms by which these oncoproteins affect NF kappa B signaling downstream of TNF.
  • To determine if the observed effects are dependent on known signaling pathways like Raf, PI3-kinase, or MEK.

Main Methods:

  • Expression of BCR-ABL in 32D myeloid cells and oncogenic Ras in murine fibroblasts.
  • Treatment with TNF to assess NF kappa B activation.
  • Measurement of inhibitor of NF kappa B (IKK) activity, NF kappa B DNA binding, and nuclear translocation of NF kappa B/p65.
  • Analysis of NF kappa B-dependent gene expression (iNOS, RANTES).
  • Investigation of signaling pathways including Raf, PI3-kinase, and MEK.

Main Results:

  • BCR-ABL and oncogenic Ras expression suppressed TNF-induced NF kappa B activation.
  • This suppression involved inhibition of TNF-induced IKK activity and NF kappa B DNA binding, but not nuclear accumulation of NF kappa B/p65.
  • The inhibitory effect was not observed in oncogenic Raf-expressing cells and was not fully rescued by inhibiting PI3-kinase or MEK.
  • Oncogenic Ras reduced the expression of NF kappa B-dependent genes like iNOS and RANTES upon TNF stimulation.

Conclusions:

  • Ras and BCR-ABL oncoproteins interfere with TNF-induced NF kappa B activation through a mechanism that does not involve canonical IKK activity.
  • These oncoproteins suppress the TNF-induced IKK pathway via a Raf/MEK/Erk-independent route.
  • The findings suggest an uncharacterized pathway utilized by Ras and BCR-ABL to modulate NF kappa B signaling, impacting oncogenic transformation.

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