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J. Biol. Chem., Vol. 283, Issue 29, 20137-20148, July 18, 2008

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PIASy Represses CCAAT/Enhancer-binding Protein (C/EBP) Transcriptional Activity by Sequestering C/EBP to the Nuclear Periphery^*

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

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