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Originally published In Press as doi:10.1074/jbc.M801307200 on May 12, 2008

J. Biol. Chem., Vol. 283, Issue 29, 20137-20148, July 18, 2008
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PIASy Represses CCAAT/Enhancer-binding Protein {delta} (C/EBP{delta}) Transcriptional Activity by Sequestering C/EBP{delta} to the Nuclear Periphery*

Shanggen Zhou, Junling Si1, Tong Liu1, and James W. DeWille2

From the Ohio State Biochemistry Program, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210

CCAAT/enhancer binding protein{delta} (C/EBP{delta}) plays a key role in mammary epithelial cell G0 growth arrest, and "loss of function" alterations in C/EBP{delta} have been reported in breast cancer and acute myeloid leukemia. C/EBP{delta} is regulated at the transcriptional, post-transcriptional, and post-translational levels, suggesting tight control of C/EBP{delta} 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, PIASxβ, and PIASy, and all three PIAS family members repress C/EBP{delta} transcriptional activity. PIASy is the most potent, however, repressing C/EBP{delta} transcriptional activity by >80%. PIASy repression of C/EBP{delta} transcriptional activity is dependent upon interaction between the highly conserved PIASy N-terminal nuclear matrix binding domain (SAPD) and the C/EBP{delta} transactivation domain (TAD). PIASy repression of C/EBP{delta} transcriptional activity is independent of histone deacetylase activity, PIASy E3 SUMO ligase activity, and C/EBP{delta} sumoylation status. PIASy expression is associated with C/EBP{delta} translocation from nuclear foci, where C/EBP{delta} co-localizes with p300, to the nuclear periphery. PIASy-mediated translocation of C/EBP{delta} is dependent upon the PIASy SAPD and C/EBP{delta} TAD. PIASy reduces the expression of C/EBP{delta} 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/EBP{delta} by a mechanism that requires interaction between the PIASy SAPD and C/EBP{delta} TAD and does not require PIASy SUMO ligase activity or C/EBP{delta} sumoylation. PIASy alters C/EBP{delta} nuclear localization, reduces C/EBP{delta} transcriptional activity, and enhances cell proliferation/migration.


Received for publication, February 19, 2008 , and in revised form, May 1, 2008.

* This work was supported, in whole or in part, by National Institutes of Health Grants CA57607-14 (to J. D.) and P30 CA16058 (to The Ohio State University). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Both of these authors contributed equally to this work.

2 To whom correspondence should be addressed: Dept. of Veterinary Biosciences, 1925 Coffey Rd., Columbus, OH 43210-1093. Tel.: 614-292-4261; Fax: 614-292-6473; E-mail: dewille.1{at}osu.edu.


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