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NFI-Ski interactions mediate transforming growth factor beta modulation of human papillomavirus type 16 early gene

Amy Baldwin1, Lucia Pirisi, Kim E Creek

  • 1Department of Pathology and Microbiology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA.

Journal of Virology
|March 30, 2004
PubMed

Insights

Transforming growth factor beta (TGF-beta) inhibits human papillomavirus type 16 (HPV16) early gene expression by reducing Ski protein levels, which decreases nuclear factor I (NFI) activity.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Human papillomaviruses (HPVs), particularly HPV type 16 (HPV16), are implicated in cervical cancer development.
  • Loss of sensitivity to transforming growth factor beta (TGF-beta) is crucial for malignant progression.
  • HPV16 early gene expression, controlled by the upstream regulatory region (URR), is normally inhibited by TGF-beta.

Purpose of the Study:

  • To identify transcription factors and binding sites in the HPV16 URR involved in TGF-beta-mediated regulation.
  • To elucidate the molecular mechanism by which TGF-beta inhibits HPV16 early gene expression.

Main Methods:

  • DNase I footprinting and electrophoretic mobility shift assays (EMSA) on the HPV16 URR.
  • Nuclear factor I (NFI) and Ski protein/mRNA level analysis.
  • Mutational analysis of NFI binding sites within the URR.
  • Co-immunoprecipitation assays to assess NFI-Ski interaction.

Main Results:

  • TGF-beta treatment decreased NFI binding to its sites within the HPV16 URR, independent of NFI protein or mRNA levels.
  • Mutations in NFI binding sites affected TGF-beta sensitivity.
  • Overexpression of NFI family members reduced TGF-beta's inhibitory effect.
  • TGF-beta treatment decreased cellular Ski levels, and Ski overexpression abrogated TGF-beta's inhibition.
  • NFI and Ski were found to interact in HPV16-immortalized keratinocytes.

Conclusions:

  • TGF-beta inhibits HPV16 early gene expression by reducing Ski protein levels.
  • The decrease in Ski leads to reduced NFI activity.
  • This Ski-NFI pathway is the mechanism by which TGF-beta modulates the HPV16 URR.

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