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J. Biol. Chem., Vol. 281, Issue 27, 18451-18462, July 7, 2006

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Post-transcriptional Control of Cited2 by Transforming Growth Factor

REGULATION VIA SMADS AND CITED2 CODING REGION^*

From the Department of Pharmacology and Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4965

Cited2 is a transcription factor without typical DNA binding domains. Cited2 interacts with cAMP-responsive element-binding protein-binding protein (CBP)/p300, TFAP2, Lhx2, and nuclear receptors, such as peroxisome proliferator-activated receptor and estrogen receptor to function as a transcriptional modulator. Overexpression of Cited2 in Rat1 cells leads to tumor formation in nude mice, suggesting that Cited2 is a transforming gene. Through microarray analysis, Cited2 was found to be down-regulated by transforming growth factor 1 (TGF-) in various cell lines. In this study, we confirmed that both mRNA and protein levels of Cited2 are down-regulated in MDA-MB-231 breast cancer cells. Overexpression of Smad7 or knockdown of Smad4 in MDA-MB-231 cells showed that the Smad pathway is involved in the down-regulation of Cited2. Based on nuclear run-on analysis and Cited2 promoter/reporter assay, Cited2 transcription was not affected by TGF-, supporting that down-regulation of Cited2 by TGF- is most likely through post-transcriptional regulation. By using transcriptional inhibitors, we demonstrated that the turnover of Cited2 transcripts appears to be accelerated during TGF- stimulation. Pharmacologic inhibition of translation with cycloheximide attenuated Cited2 down-regulation by TGF-. We examined the expression of recombinant Cited2 gene introduced into MDA-MB-231 cells by stable transfection, and we found that mRNA containing the Cited2 protein-coding region controlled by a heterologous promoter indeed responds to TGF--mediated down-regulation. Study from Cited2 deletion mutants showed that the C-terminal conserved region of Cited2 coding sequence is essential for the down-regulation. This is the first demonstration that TGF--mediated down-regulation of Cited2 is post-transcriptional, through the Smad pathway, and requires the presence of its coding sequence.

Received for publication, February 22, 2006 , and in revised form, May 2, 2006.

^* This work was supported by National Institutes of Health Grants RO1 HL48819 and RO1 CA78433 (to Y. C. Y.). 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 To whom correspondence should be addressed: Dept. of Pharmacology, Case Western Reserve University School of Medicine, 2109 Adelbert Rd., W353, Cleveland, OH 44106-4965. Tel.: 216-368-6931; Fax: 216-368-3395; E-mail: yxy36{at}cwru.edu.

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