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J. Biol. Chem., Vol. 280, Issue 7, 5588-5597, February 18, 2005

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Structure and Regulation of the Murine Reduced Folate Carrier Gene

IDENTIFICATION OF FOUR NONCODING EXONS AND PROMOTERS AND REGULATION BY DIETARY FOLATES^*

Mingjun Liu, Yubin Ge, Diane C. Cabelof¶, Amro Aboukameel, Ahmad R. Heydari¶, Ramzi Mohammad, and Larry H. Matherly||

From the Experimental and Clinical Therapeutics Program, Barbara Ann Karmanos Cancer Institute, the Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201, and the ^¶Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan 48201

The upstream structure and regulation of the mouse reduced folate carrier (mRFC) gene was characterized. By 5'-rapid amplification of cDNA ends assay and DNA sequencing from mouse tissues and 7–15-day stage embryos, mRFC transcripts with four unique 5' noncoding exons, designated mRFC-a,-b,-c, and -d, were identified mapping over 6300 bp. The 5' noncoding exons were characterized by multiple transcription starts and, for form b, two alternate splice forms. mRFC transcript forms were measured by real-time reverse transcription-PCR in mouse tissues and embryos and in L1210 leukemia and BNL CL.2 liver cell lines. The highest mRFC levels were detected in kidney and brain. mRFC-b and -c were the major transcript forms, with low levels of mRFC-a and -d. The 5'-flanking regions for exons a–d each exhibited promoter activity in reporter gene assays. mRFC transcripts and individual noncoding exons were measured in small intestine and kidney from mice fed folate-deficient or -replete diets. Mice fed the folate-deficient diet exhibited a significant (13.8-fold) increase in total mRFC transcripts and protein in the small intestine, reflecting increases in each of the mRFC-b, -c, and -d forms. Only minor changes in mRFC transcript levels or distributions were detected for kidney. Levels of folate-binding protein were also increased in both small intestine and kidney in folate-deficient mice (91- and 2-fold, respectively). Multidrug resistance-associated proteins 1 and 3 were, likewise, elevated in intestine from folate-deficient mice (53- and 168-fold, respectively); however, there were no significant changes in kidney. Our results document the existence of four unique noncoding exons and promoters for mRFC and demonstrate a facile induction of mRNAs for mRFC and multidrug resistance-associated proteins 1 and 3 in intestine in response to changes in dietary folate intake.

Received for publication, November 9, 2004 , and in revised form, November 23, 2004.

^* This study was supported by NCI, National Institutes of Health, Grant CA53535. 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) AY73445, AY734486, and AY734487, and U57780.

^|| To whom correspondence should be addressed: Experimental and Clinical Therapeutics Program, Karmanos Cancer Institute, 110 E. Warren Ave., Detroit, MI 48201. Tel.: 313-833-0715 (ext. 2407); Fax: 313-832-7294; E-mail: matherly{at}karmanos.org.

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