White, N.R.; Mulligan, P.; King, P.J.; Sanderson, I.R.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA50
Academic Journal
Introduction: Butyrate induces histone acetylation, but this does not easily explain the down-regulation of hlGFBP-3 by butyrate, as histone acetylation is associated with expansion of the nucleosome. Furthermore, the down regulation occurs in the absence of de novo protein synthesis, excluding the induction of a repressor as a possible mechanism. However, promoter analysis revealed the presence of a butyrate responsive element that included binding sites for p300 and Sp1/Sp3. Methods: We examined the acetylation and activity of Sp3 in hlGFBP-3 expression. Results: Transfection of Caco-2 cells with E1A, an inhibitor of p300 acetyltransferase activity, reversed the butyrate induced repression of hlGFBP-3. Sp3 is a known repressor of gene activation. Its potential for acetylation has recently been reported. We hypothesized that butyrate might increase the acetylation of Sp3. We, therefore, performed EMSA and supershift studies on nuclear extracts from butyrate treated and non-treated Caco-2 cells with the hIGFBP-3 promoter. We also studied nuclear extracts by Western blotting analysis and immunoprecipitation. 5mM butyrate retarded the Sp3-specific band in EMSAs. This band was further supershifted by an anti-acetyl lysine-specific antibody. Immunoprecipitation indicated an increase in the amount of the acetylated form of Sp3, in the presence of NaB, whereas the total amount of Sp3 protein was unchanged. Western blot analysis revealed the acetylation of an isoform of Sp3 in the presence of 5mM NaB. Transfection with E1A abrogated the repression by NaB as evidenced by semi-quantitative PCR and Western blot analysis. Conclusions: Our evidence supports the hypothesis that butyrate down-regulates hlGFBP-3 by butyrate by the acetylation of the repressor Sp3 and likely involves p300. We have shown for the first time that butyrate affects the acetylation status of a non-histone DNA-binding protein.


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