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J. Biol. Chem., Vol. 276, Issue 28, 25742-25752, July 13, 2001

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Sodium Butyrate Induces Transcription from the G_i2 Gene Promoter through Multiple Sp1 Sites in the Promoter and by Activating the MEK-ERK Signal Transduction Pathway^*

Jianqi Yang, Yumiko Kawai, Richard W. Hanson, and Ifeanyi J. Arinze^§

From the Department of Biochemistry, Meharry Medical College, Nashville, Tennessee 37208-3599 and the  Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935

Sodium butyrate, an erythroid differentiation inducer and a histone deacetylase inhibitor, increases G_i2 levels in differentiating K562 cells. Here we show that sodium butyrate induces G_i2 gene transcription via sequences at 50/36 and 92/85 in the G_i2 gene promoter. Both sequences contain core sequence motif for Sp1 binding; electrophoretic mobility shift as well as supershift assays confirmed binding to Sp1. Transcription from the G_i2 gene promoter was also activated by two other histone deacetylase inhibitors, trichostatin A and Helminthsporium carbonium toxin (HC toxin), which also induce erythroblastic differentiation in K562 cells. However, hydroxyurea, a potent erythroid differentiation inducer in these cells, did not activate transcription from this gene promoter, indicating that promoter activation is inducer-specific. Mutations within the Sp1 sites at 50/36 and 92/85 in the G_i2 gene promoter substantially decreased transcriptional activation by sodium butyrate, trichostatin A, or HC toxin. Transfection with constitutively activated ERKs indicated that this promoter can be activated through the MEK-ERK signal transduction pathway. Inhibition of the MEK-ERK pathway with U0126 or reduction in the expression of endogenous ERK with an antisense oligonucleotide to ERK significantly inhibited sodium butyrate- and HC toxin-induced transcription but had no effect on trichostatin A-induced transcription. Inhibition of the JNK and p38 MAPKs, using selective inhibitors, had no effect on sodium butyrate-induced transcription. In cells in which sodium butyrate induction of promoter activation had been inhibited by various concentrations of U0126, constitutively activated ERK2 reversed this inhibition. These results show that the MEK-ERK signal transduction pathway is important in butyrate signaling, which eventually converges in the cell nucleus.

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