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PIASy represses CCAAT/enhancer-binding protein delta (C/EBPdelta) transcriptional activity by sequestering C/EBPdelta

Shanggen Zhou1, Junling Si, Tong Liu

  • 1Ohio State Biochemistry Program, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.

The Journal of Biological Chemistry
|May 15, 2008
PubMed

Insights

Protein Inhibitors of Activated STATs (PIAS) family member PIASy represses CCAAT/enhancer binding protein delta (C/EBPdelta) activity. PIASy alters C/EBPdelta localization, reducing its transcriptional activity and promoting cell migration.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • CCAAT/enhancer binding protein delta (C/EBPdelta) is crucial for mammary epithelial cell G(0) growth arrest and is implicated in breast cancer and acute myeloid leukemia.
  • C/EBPdelta function is tightly regulated at multiple levels, including transcriptional, post-transcriptional, and post-translational modifications.
  • Protein Inhibitors of Activated STATs (PIASs) are known regulators of transcription factors, including C/EBPs.

Purpose of the Study:

  • To investigate the role of PIAS family members, specifically PIASy, in regulating C/EBPdelta transcriptional activity and cellular function.
  • To elucidate the mechanism by which PIASy represses C/EBPdelta activity.
  • To determine the impact of PIASy on C/EBPdelta localization and its downstream effects on cell behavior.

Main Methods:

  • Utilized HC11 nontransformed mammary epithelial cells expressing PIAS3, PIASxbeta, and PIASy.
  • Assessed the impact of PIAS family members on C/EBPdelta transcriptional activity.
  • Investigated the interaction domains between PIASy and C/EBPdelta using their N-terminal nuclear matrix binding domain (SAPD) and transactivation domain (TAD).
  • Examined the effect of PIASy on C/EBPdelta nuclear localization and co-localization with p300.
  • Evaluated the influence of PIASy on C/EBPdelta target gene expression and cell migration using an in vitro scratch assay.

Main Results:

  • All three PIAS family members (PIAS3, PIASxbeta, PIASy) repressed C/EBPdelta transcriptional activity, with PIASy being the most potent (>80% repression).
  • PIASy repression of C/EBPdelta activity was dependent on the interaction between the PIASy SAPD and C/EBPdelta TAD, independent of SUMO ligase activity or C/EBPdelta sumoylation status.
  • PIASy expression induced C/EBPdelta translocation from nuclear foci to the nuclear periphery, altering its co-localization with p300.
  • PIASy reduced the expression of C/EBPdelta adhesion-related target genes and enhanced cell migration in a scratch assay.

Conclusions:

  • PIASy effectively represses C/EBPdelta transcriptional activity through a mechanism involving the PIASy SAPD and C/EBPdelta TAD interaction.
  • This repression is independent of PIASy's SUMO ligase activity and C/EBPdelta's sumoylation status.
  • PIASy modulates C/EBPdelta's nuclear localization, leading to decreased transcriptional activity and enhanced cell proliferation/migration, suggesting a role in cancer progression.

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