The Transcription Factor SP3 Drives TNF-α Expression in Response to Smac Mimetics

Sci Signal. 2019 Jan 29;12(566):eaat9563. doi: 10.1126/scisignal.aat9563.

Abstract

The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α-contrary to what its name implies-leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in cancer cells. Using a genome-wide siRNA screen to identify factors required for SMC-to-TNF-α-mediated cancer cell death, we identified the transcription factor SP3 as a critical molecule in both basal and SMC-induced production of TNF-α by engaging the nuclear factor κB (NF-κB) transcriptional pathway. Moreover, the promotion of TNF-α expression by SP3 activity confers differential sensitivity of cancer versus normal cells to SMC treatment. The key role of SP3 in TNF-α production and signaling will help us further understand TNF-α biology and provide insight into mechanisms relevant to cancer and inflammatory disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Biomimetic Materials / pharmacology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mice
  • Mitochondrial Proteins / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • RNA Interference
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Sp3 Transcription Factor / genetics
  • Sp3 Transcription Factor / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Inhibitor of Apoptosis Proteins
  • Mitochondrial Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Sp3 Transcription Factor

Grant support