IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes.
Beta-site APP cleaving enzyme 1 (BACE1) is an essential enzyme for the production of beta amyloid. Since we found that injection of interferon-gamma (IFN-gamma) into young mouse brains increased BACE1 expression in astrocytes, we investigated molecular mechanisms underlying this process by cloning a putative BACE1 promoter. BACE1 promoter activity was differentially regulated by IFN-gamma in a region specific manner and down-regulated by an inhibitor of Janus kinase 2 (JAK2). A dominant negative mutant of signal transducer and activator of transcription 1 (STAT1) expression suppressed BACE1 promoter activity, and this was rescued by transfecting wild type STAT1. Electrophoretic mobility shift assay and promoter activity assays indicated that STAT1 binds directly to the putative STAT1 binding sequence of BACE1 promoter. Because IFN-gamma treatment induced STAT1 phosphorylation, we examined whether the expression of a suppressor of cytokine signaling (SOCS), negative regulator of JAK2, suppresses BACE1 promoter activity. The results show that SOCS1 or SOCS3 expression suppressed BACE1 promoter by blocking phosphorylation of Tyr701 residue in STAT1. Also, because IFN-gamma treatment specifically potentiated extracellular signal regulated MAP kinase (ERK) 1/2 activation, pretreatment of mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, PD98059, significantly attenuated IFN-gamma-induced BACE1 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in STAT1, suggesting that ERK1/2 is associated with IFN-gamma-induced STAT1 signaling cascade. Taken together, our results suggest that IFN-gamma activates JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region to modulate BACE1 protein expression in astrocytes.
Cho
Hyun Jin
HJ
Department of Biochemistry and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Kim
Su-Kyoung
SK
Jin
Seok Min
SM
Hwang
Eun-Mi
EM
Kim
Yong Sik
YS
Huh
Kyoon
K
Mook-Jung
Inhee
I
D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000201:enzymology* / Q000276:immunology; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D004791:Enzyme Inhibitors; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D048052:Mitogen-Activated Protein Kinase 3; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human