title: The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway.
abstract: Acid alpha-glucosidase (GAA) is a lysosomal enzyme that degrades glycogen. A deficiency of GAA is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenosis type II. Previously, we identified an intronic repressor element in the GAA gene and demonstrated that Hes-1, a basic helix-loop-helix factor, binds to a C class E box within the element and functions as a transcriptional repressor in HepG2 cells. Hes-1 is a well studied downstream target gene in the Notch signaling pathway. In this study, over-expression and depletion of Notch-1 intracellular domain (NICD) strategies were used to investigate whether expression of the GAA gene is under the control of Notch-1/Hes-1 signaling. In co-transfection experiments, Hes-1, up-regulated by over-expressed NICD, enhanced the repressive effect of the DNA element with wild type Hes-1 binding sites but not with mutant Hes-1 binding sites. Conversely, depletion of Notch-1 with phosphorothioated antisense oligonucleotides, corresponding to the fourth ankyrin repeat within NICD, led to reduced Hes-1. Constitutively over-expressed Hes-1 and Notch-1 repressed GAA gene expression. Therefore, our data establish that the human GAA gene, encoding a lysosomal enzyme, is a downstream target of the Notch-1/Hes-1 signaling pathway.
authors.affiliation: Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1820, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Paul
authors.initials: P
authors.lastname: Plotz
mesh_terms: D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D017931:DNA Primers; D018398:Homeodomain Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins; D011506:Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D014157:Transcription Factors; D000520:alpha-Glucosidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000520:alpha-Glucosidases; C489737:GAD3 protein, human