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Published online October 6, 2008
doi:10.1083/jcb.200806172
The Journal of Cell Biology, Vol. 183, No. 1, 49-61
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Stanya et al.
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Article

Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT



Kristopher J. Stanya1, Yu Liu1, Anthony R. Means2, and Hung-Ying Kao1

1 Department of Biochemistry, School of Medicine, Case Western Reserve University, Research Institute of University Hospitals of Cleveland, Cleveland, OH 44106
2 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710

Correspondence to H.-Y. Kao: hxk43{at}case.edu

Silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) is a transcriptional corepressor that participates in diverse signaling pathways and human diseases. However, regulation of SMRT stability remains largely unexplored. We show that the peptidyl-prolyl isomerase Pin1 interacts with SMRT both in vitro and in mammalian cells. This interaction requires the WW domain of Pin1 and SMRT phosphorylation. Pin1 regulates SMRT protein stability, thereby affecting SMRT-dependent transcriptional repression. SMRT phosphorylation at multiple sites is required for Pin1 interaction, and these sites can be phosphorylated by Cdk2, which interacts with SMRT. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability, whereas mutation of these phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Finally, decreases in SMRT stability occur in response to the activation of Her2/Neu/ErbB2, and this receptor functions upstream of both Pin1 and Cdk2 in the signaling cascade that regulates SMRT stability and cellular response to tamoxifen.

Abbreviations used in this paper: CHX, cycloheximide; DBD, DNA-binding domain; DN, dominant negative; HDAC, histone deacetylase; MEF, mouse embryonic fibroblast; N-CoR, nuclear receptor corepressor; PPIase, peptidyl-prolyl isomerase; PR, progesterone receptor; pS-P, phospho-Ser-Pro; pT-P, phospho-Thr-Pro; RD, repression domain; SMRT, silencing mediator for retinoic acid and thyroid hormone receptor; WCE, whole cell extract; WT, wild type.

© 2008 Stanya et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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