E2F1 regulation of the human myo-inositol 1-phosphate synthase (ISYNA1) gene promoter.
Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate. It is a potential target for mood-stabilizing drugs such as lithium and valproate. But, very little is known about the regulation of human IP synthase. Here, we have characterized the minimal promoter of ISYNA1 and show that it is upregulated by E2F1. Upregulation occurs in a dose-dependent fashion and can be suppressed by ectopic expression of Rb. EMSA and antibody supershift analysis identified a functional E2F binding motif at -117. Complex formation at this site was competed by an excess of unlabeled Sp1 oligo consistent with the -117 E2F site overlapping an Sp1 motif. Because the -117 E2F motif is not a high-affinity binding site, we propose that the upregulation of ISYNA1 occurs through the cooperative interaction of several low-affinity E2F binding motifs present in the minimal promoter.
Molecular Neuroscience and Bioinformatics Laboratories, Mental Health, Behavioral Science and Research Services, VA Medical Center (151), Louisville, KY 40206, USA.
Ratnam S
RS
Seelan
Latha K
LK
Parthasarathy
Ranga N
RN
Parthasarathy
D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D008969:Molecular Sequence Data; D007296:Myo-Inositol-1-Phosphate Synthase / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D007295:Inositol Phosphates; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C002647:inositol 1-phosphate; D007296:Myo-Inositol-1-Phosphate Synthase