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Transactivation via RAR/RXR-Sp1 Interaction: Characterization of Binding Between Sp1 and GC Box Motif

Laboratory of Molecular Cell Sciences, Tsukuba Institute, RIKEN, Koyadai, Tsukuba, Ibaraki 305-0074, Japan (J.S., Y.S., S.K.); Institute of Applied Biochemistry, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305-0006, Japan (J.S., Y.S., P.-C.W., M.M.); and Laboratory of Cell Regulation and Carcinogenesis, Division of Basic Science, National Cancer Institute, National Institute of Health, Bethesda, Maryland 20892 (S.-J.K.)

Address all correspondence and requests for reprints to: Soichi Kojima, Ph.D., Laboratory of Molecular Cell Sciences, Tsukuba Institute, RIKEN, Koyadai, Tsukuba, Ibaraki 305-0074, Japan. E-mail: kojima{at}rtc.riken.go.jp

Modulation of Sp1 activity by nuclear receptors is a novel mechanism by which fat-soluble hormones regulate gene expression. We previously established that upon autoinduction of RARs by RA, RARs/RXRs physically interact with Sp1, potentiate Sp1 binding to the GC box motifs, and thus enhance transactivation of the urokinase promoter, which lacks a canonical RAR-responsive element/RXR-responsive element. Here, we examined whether a similar mechanism might participate in transcriptional regulation of other key RA-inducible genes in endothelial cells and characterized binding between Sp1 and GC box motifs. Northern blot analyses showed that in addition to urokinase, after induction of RARs, RA up-regulates GC-rich region-dependent mRNA expression of transglutaminase, TGFß1, and types I and II TGFß receptors. RA failed to alter the expression of Sp1 at both mRNA and protein levels. Reporter and gel shift assays and Western blot analyses suggested that either RA-treatment or RAR/RXR-overexpression enhances transactivation of these genes through a GC-rich region and strengthens the affinity of Sp1 to GC box motifs, accompanying a potential conformational change of Sp1 as reflected in its increased immunogenicity. Detailed analyses of the GC box motifs within the urokinase and other promoters indicate that interaction between RAR/RXR and Sp1 does not occur in the presence of nonfunctional GC box motifs containing five tandem purine or pyrimidine bases at the 3'-flanking region of hexanucleotide core sequence. These findings provide insight into the molecular mechanisms underlying RARE/RXRE-independent transactivation of RA-inducible gene promoters.

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