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Background  Choline kinase is the most upstream enzyme in the CDP-choline pathway. It catalyzes the phosphorylation of choline to phosphorylcholine in the presence of ATP and Mg 2+  during the biosynthesis of phosphatidylcholine, the major phospholipid in eukaryotic cell membranes. In humans, choline kinase (CK) is encoded by two separate genes,  ckα  and  ckβ , which produce three isoforms, CKα1, CKα2, and CKβ. Previous studies have associated  ckβ  with muscle development; however, the molecular mechanism underlying the transcriptional regulation of  ckβ  has never been elucidated.    Methodology/Principal Findings  In this report, the distal promoter region of the  ckβ  gene was characterized. Mutational analysis of the promoter sequence and electrophoretic mobility shift assays (EMSA) showed that Ets and GATA transcription factors were essential for the repression of  ckβ  promoter activity. Supershift and chromatin immunoprecipitation (ChIP) assays further identified that GATA3 but not GATA2 was bound to the GATA site of  ckβ  promoter. In addition, phorbol-12-myristate-13-acetate (PMA) decreased  ckβ  promoter activity through Ets and GATA elements. PMA also decreased the  ckβ  mRNA and protein levels about 12 hours after the promoter activity was down-regulated. EMSA further revealed that PMA treatment increased the binding of both Ets and GATA transcription factors to their respective DNA elements. The PMA-mediated repressive effect was abolished by chronic PMA treatment and by treatment with the PKC inhibitor PKC412, but not the PKC inhibitor Go 6983, suggesting PKCε or PKCη as the PKC isozyme involved in the PMA-mediated repression of  ckβ  promoter. Further confirmation by using PKC isozyme specific inhibitors identified PKCε as the isozyme that mediated the PMA repression of  ckβ  promoter.    Conclusion/Significance  These results demonstrate the participation of the PKC signaling pathway in the regulation of  ckβ  gene transcription by Ets and GATA transcription factors.

Ets and GATA Transcription Factors Play a Critical Role in PMA-Mediated Repression of the ckβ Promoter via the Protein Kinase C Signaling Pathway