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Interferon regulatory factor-1 regulates reconstituted extracellular matrix (rECM)-mediated apoptosis in human

M L Bowie1, M M Troch, J Delrow

  • 1Department of Medicine, Duke University, Durham, NC 27710, USA.

Oncogene
|October 4, 2006
PubMed

Insights

Extracellular matrix (ECM) and tamoxifen signaling induce apoptosis in mammary epithelial cells by activating Interferon regulatory factor-1 (IRF-1). This IRF-1 activation involves CREB-binding protein (CBP) recruitment to the IRF-1 promoter, highlighting a shared pathway for cell death signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mammary gland homeostasis relies on extracellular matrix (ECM) and epithelial cell interactions.
  • Interferon regulatory factor-1 (IRF-1) regulates apoptosis during mammary gland involution.
  • Previous work showed tamoxifen (Tam) signaling induces apoptosis in damaged human mammary epithelial cells (*HMEC-E6) via IRF-1, CREB-binding protein (CBP), and caspase activation.

Purpose of the Study:

  • To investigate if reconstituted ECM (rECM) also induces apoptosis in *HMEC-E6 cells.
  • To elucidate the molecular mechanisms of rECM-mediated apoptosis.
  • To determine if rECM and Tam signaling share a common pathway for IRF-1 transcriptional activation.

Main Methods:

  • Treatment of *HMEC-E6 cells with growth factor-depleted rECM.
  • Analysis of CBP recruitment to the IRF-1 promoter's gamma-activating sequence (GAS) element.
  • Measurement of IRF-1, caspase-1, and caspase-3 expression.
  • Small interfering RNA (siRNA)-mediated knockdown of IRF-1.

Main Results:

  • rECM induced apoptosis in *HMEC-E6 cells, mirroring Tam signaling effects.
  • Apoptosis correlated with CBP recruitment to the IRF-1 GAS promoter, IRF-1 induction, and caspase activation.
  • IRF-1 suppression by siRNA abrogated rECM-induced IRF-1 expression, caspase activation, and apoptosis.

Conclusions:

  • IRF-1 is essential for rECM-mediated apoptosis in *HMEC-E6 cells.
  • Both rECM and Tam signaling activate IRF-1 transcriptionally via CBP recruitment to the IRF-1 GAS promoter.
  • This study reveals a conserved mechanism for apoptosis induction by distinct signaling pathways in mammary epithelial cells.

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