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J. Biol. Chem., Vol. 280, Issue 19, 19373-19380, May 13, 2005

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Identification of Transcriptional Targets of HOXA5^*

Hexin Chen, Ethel Rubin, Huiping Zhang, Seung Chung, Charles C. Jie, Elizabeth Garrett, Shyam Biswal¶, and Saraswati Sukumar||

From the Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland 21231-1000 and the Department of Biostatistics and Clinical Trials, ^¶Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland 21205

The homeobox gene HOXA5 encodes a transcription factor that has been shown to play important roles in embryogenesis, hematopoiesis, and tumorigenesis. In order to decipher downstream signaling pathways of HOXA5, we utilized oligonucleotide microarray analysis to identify genes that are differentially expressed in HOXA5-induced cells compared with uninduced cells. Comparative analysis of gene expression changes after 9 h of HOXA5 induction in Hs578T breast cancer cells identified 306 genes whose expression was modulated at least 2-fold. Ten of these 306 genes were also up-regulated by at least 2-fold at 6 h post-induction. The expression of all of these 10 genes was confirmed by semiquantitative reverse transcription-PCR. Among these 10 genes, which are most likely to be direct targets of HOXA5, we initiated an investigation into the pleiotrophin gene by first cloning its promoter. Transient transfection assays indicated that HOXA5 can specifically activate the pleiotrophin promoter. Promoter deletion, chromatin immunoprecipitation assay, and gel-shift assays were performed to show that HOXA5 can directly bind to one binding site on the pleiotrophin promoter. These data strongly suggest that microarray analysis can successfully identify many potential direct downstream genes of HOXA5. Further functional analysis of these targets will allow us to better understand the diverse functions of HOXA5 in embryonic development and tumorigenesis.

Received for publication, December 1, 2004 , and in revised form, February 15, 2005.

^* This work was supported by Susan Komen Fellowship PDF0100603 (to H. C.) and SPORE Grant P50CA88843 from the National Institutes of Health (to S. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1-4.

^|| To whom correspondence should be addressed: Comprehensive Cancer Center, The Johns Hopkins Hospital, 1650 Orleans St., CRB410, Baltimore, MD 21231-1000. Tel.: 410-614-2479; Fax: 410-614-4073; E-mail: saras{at}jhmi.edu.

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