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PIASy represses CCAAT/enhancer-binding protein delta (C/EBPdelta) transcriptional activity by sequestering C/EBPdelta to the nuclear periphery.

CCAAT/enhancer binding proteindelta (C/EBPdelta) plays a key role in mammary epithelial cell G(0) growth arrest, and "loss of function" alterations in C/EBPdelta have been reported in breast cancer and acute myeloid leukemia. C/EBPdelta is regulated at the transcriptional, post-transcriptional, and post-translational levels, suggesting tight control of C/EBPdelta content and function. Protein inhibitors of activated STATs (PIASs) regulate a growing number of transcription factors, including C/EBPs. HC11 nontransformed mammary epithelial cells express PIAS3, PIASxbeta, and PIASy, and all three PIAS family members repress C/EBPdelta transcriptional activity. PIASy is the most potent, however, repressing C/EBPdelta transcriptional activity by >80%. PIASy repression of C/EBPdelta transcriptional activity is dependent upon interaction between the highly conserved PIASy N-terminal nuclear matrix binding domain (SAPD) and the C/EBPdelta transactivation domain (TAD). PIASy repression of C/EBPdelta transcriptional activity is independent of histone deacetylase activity, PIASy E3 SUMO ligase activity, and C/EBPdelta sumoylation status. PIASy expression is associated with C/EBPdelta translocation from nuclear foci, where C/EBPdelta co-localizes with p300, to the nuclear periphery. PIASy-mediated translocation of C/EBPdelta is dependent upon the PIASy SAPD and C/EBPdelta TAD. PIASy reduces the expression of C/EBPdelta adhesion-related target genes and enhances repopulation of open areas within a cell monolayer in the in vitro "scratch" assay. These results demonstrate that PIASy represses C/EBPdelta by a mechanism that requires interaction between the PIASy SAPD and C/EBPdelta TAD and does not require PIASy SUMO ligase activity or C/EBPdelta sumoylation. PIASy alters C/EBPdelta nuclear localization, reduces C/EBPdelta transcriptional activity, and enhances cell proliferation/migration.

Pubmed ID: 18477566

Authors

  • Zhou S
  • Si J
  • Liu T
  • DeWille JW

Journal

The Journal of biological chemistry

Publication Data

July 18, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA 57607-14
  • Agency: NCI NIH HHS, Id: P30 CA 16058

Mesh Terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-delta
  • Cell Adhesion
  • Cell Line
  • Cell Movement
  • Cell Nucleus
  • Cell Proliferation
  • Gene Expression Regulation
  • Mice
  • Protein Binding
  • Protein Inhibitors of Activated STAT
  • Protein Processing, Post-Translational
  • SUMO-1 Protein
  • Trans-Activators