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J. Biol. Chem., Vol. 282, Issue 1, 49-57, January 5, 2007

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Comparative Analysis of Retroviral and Native Promoters Driving Expression of 1,3-Galactosyltransferase 3Gal-T5 in Human and Mouse Tissues^*

From the Department of Biomedical Sciences Experimental and Clinical, University of Insubria Medical School, 21100 Varese, Italy

1,3-Galactosyltransferase 3Gal-T5 is highly expressed in the colons of humans and certain primates due to a retroviral long terminal repeat (LTR) acting as a strong promoter. Because this promoter is inactive in other human tissues or mice, we attempted to understand how adoption of a retrotransposon allowed the gene to acquire tissue-specific expression. We identified three novel 5'-UTRs of 3Gal-T5 mRNA, types A, B, and C, and found widespread expression of the type A transcript at much lower levels than the LTR transcript, the expression of which is restricted to organs of the gastrointestinal tract. Expression of the type C 5'-UTR transcript was mostly restricted to the ileum, where it was expressed at high levels. We cloned the 5'-flanking regions of both types A and B 5'-UTRs, found deletion constructs functionally active as promoters, and identified CCAAT-binding factor (CBF) and hepatocyte nuclear factor 1 (HNF-1) as the principal nuclear factors controlling the promoters of types A and B 5'-UTR transcripts, respectively. The CCAAT-binding factor binding site and the entire downstream sequence driving the expression of type A transcripts in humans are structurally and functionally conserved in mice, where they constitute a unique3Gal-T5 promoter that appears to be the ancestral promoter of the gene. The HNF-1 binding motif of the second human promoter is identical to the HNF-1/Cdx binding motif of the LTR promoter but is in the antisense orientation, resulting in much lower binding affinity and promoter strength. These data may explain the successful insertion of the transposon during evolution.

Received for publication, July 13, 2006 , and in revised form, November 15, 2006.

^* This work was supported by grants from Ministero dell'Università e della Ricerca (PRIN 2004) and from the University of Insubria (FAR 2003-2005) (to M. T.). 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ645732 [GenBank] –DQ645738 [GenBank] .

¹ Supported by a fellowship from the University of Insubria. Present address: DBCM, University of Lausanne, Rue du Bugnon 9, CH-1005 Lausanne, Switzerland.

² To whom correspondence should be addressed: DSBSC, via JH Dunant 5, 21100, Varese, Italy. Tel.: 39-0332-397-160; Fax: 39-0332-397-119; E-mail: marco.trinchera{at}uninsubria.it.

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