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.
Zhou
Shanggen
S
Ohio State Biochemistry Program, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
Si
Junling
J
Liu
Tong
T
DeWille
James W
JW
D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D051379:Mice; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000145:classification / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D025842:SUMO-1 Protein / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*
D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; D015534:Trans-Activators; D051743:CCAAT-Enhancer-Binding Protein-delta