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GATA and FOG2 transcription factors differentially regulate the promoter for Kv4.2 K(+) channel gene in cardiac myocytes and PC12 cells.

Ying Jia, Koichi Takimoto

Cardiovasc. Res., 2003 Nov 1 , 60, 278-87

OBJECTIVE: Kv4.2 subunits are major components of transient outward K(+) channels in cardiac myocytes and somatodendritic A-type channels in neurons. To identify molecular mechanisms underlying transcriptional regulation of Kv4.2 gene, we have isolated and characterized the promoter for the rat Kv4.2 gene. METHODS: PCR-based amplification of cDNA end (5'RACE) and RNase protection assays were used to determine transcription start sites. Transient transfection of Kv4.2 promoter-luciferase reporter constructs into neonatal cardiac myocytes and PC12 cells was employed to measure activity of the Kv4.2 promoter. Cotransfection of expression vectors for the transcription factors, GATA and/or FOG2, was performed to determine the effects of these transcription factors on the Kv4.2 promoter. RESULTS: Transcription of the gene initiates at 552 bp upstream from the translation initiation site in the brain and heart. Deletion analysis revealed that the approximately 200-bp fragment encompassing this start site drives significant transcription in neonatal cardiac myocytes and PC12 cells. The transcription factors GATA4 and 6 differentially enhance activity of the minimum promoter in the two cell types: GATA4 produces a larger increase than GATA6 in cardiac myocytes, whereas the latter results in a more substantial enhancement in PC12 cells. Furthermore, the coregulator of GATA, FOG2, markedly suppresses the GATA-induced increase in myocytes, but enhances it in PC12 cells. The use of GATA mutants that are incapable of forming complexes with FOG2 indicates that the formation of GATA-FOG complexes is required for the FOG2-induced suppression in myocytes, but not for the FOG2-mediated enhancement in PC12 cells. CONCLUSION: These results indicate that GATA and FOG2 transcription factors use distinct mechanisms to control the expression of Kv4.2 gene in cardiac myocytes and PC12 cells. The lack of a GATA-binding consensus sequence in the Kv4.2 minimum promoter suggests that these transcription factors indirectly influence the channel gene transcription.