Transcriptional Regulation of the Mouse Presenilin-1 Gene

Mitsuda, Noriaki; Roses, Allen D.; Vitek, Michael P.

doi:10.1074/jbc.272.38.23489

Cited by 32 publications

(22 citation statements)

References 29 publications

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“…Notably, together with the ϩ20 GC box, it is strictly conserved between the human and mouse sequences (25). Furthermore, sequences from Ϫ22 to ϩ178, which confer 80% of promoter activity, coincide with the region of high homology with the mouse promoter, and the human ϩ1 site is located only 6 nucleotides downstream from that of the mouse gene (25).…”

Section: Discussionmentioning

confidence: 99%

“…To date, the promoter of the human PS1 gene has not been mapped, and the transcription factors by which it is regulated have not been identified. A recent analysis of the mouse PS1 promoter has indicated that it is expressed only in mouse neuronal cells, suggesting that the expression of the mouse PS1 gene is tissue-specific (25). We have analyzed the promoter activity of the flanking sequences and the first exon by deletion mapping and transient expression assay in human neuroblastoma SK-N-SH cells as well as hepatoma HepG2 cells.…”

Section: Mutations Within the Presenilin (Ps)mentioning

confidence: 99%

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An Upstream Element Containing an ETS Binding Site Is Crucial for Transcription of the Human Presenilin-1 Gene

Pastorcic¹,

Das²

1999

Journal of Biological Chemistry

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Deletion mapping of the human presenilin-1 (PS1) promoter delineated the most active fragment from ؊118 to ؉178 in relation to the transcription start site mapped in this study, in both human neuroblastoma SK-N-SH and hepatoma HepG2 cells. 5 deletions revealed that a crucial element controlling over 90% of the promoter activity in these cell lines is located between ؊22 and ؊6. A mutation altering only two nucleotides of the ETS consensus sequence present at ؊12 (GGAA to TTAA) has a similar effect. Electrophoretic mobility shift assays showed that a set of specific complexes between nuclear factors and the PS1 promoter are eliminated by this point mutation, as well as by competition with an ETS consensus oligonucleotide. Competition experiments in DNase I footprinting correlated with electrophoretic mobility shift assays and showed that only one of several footprints over the PS1 promoter is eliminated by competition with an ETS consensus oligonucleotide. It extends from ؊14 to ؊6 and surrounds the ETS motif present at ؊12. Thus, a crucial ETS element is present at ؊12 and binds a protein(s) recognizing specifically the ETS consensus motif. At least one such complex is eliminated by preincubating the nuclear extract with an antibody with broad cross-reactivity with Ets-1 and Ets-2 proteins, thus confirming that an ETS transcription factor(s) recognizes the ؊12 motif. Several Sp1 binding motifs at positions ؊70, ؊55, and ؉20 surround this ETS element. Competition DNase I footprinting showed that Sp1-like nuclear factors recognize specifically these sites in both cell lines. Furthermore, a combination of 5 and 3 deletions indicated the presence of positive promoter elements between ؊96 and ؊35 as well as between ؉6 and ؉42. Thus, transfection and footprinting assays correlate to suggest that Sp1 transcription factor(s) bind at several sites upstream and downstream from the initiation site and activate the transcription of the PS1 promoter. Sequences downstream from the transcription initiation site also contain major control elements. 3 deletions from ؉178 to ؉107 decreased promoter activity by 80%. However, further deletion to ؉42 increased promoter activity by 3-4-fold. Collectively, these data indicate that sequences upstream and downstream from the transcription start site each control over 80% of the promoter activity. Hence, this suggests that protein-protein interactions between factors recognizing downstream and upstream sequences are involved.

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Section: Discussionmentioning

confidence: 99%

Section: Mutations Within the Presenilin (Ps)mentioning

confidence: 99%

An Upstream Element Containing an ETS Binding Site Is Crucial for Transcription of the Human Presenilin-1 Gene

Pastorcic¹,

Das²

1999

Journal of Biological Chemistry

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“…The promoter region was found to lack both TATA or CCAAT motifs, but contained several potential binding sites for the ubiquitous transcription factor Sp1. Extensive studies have shown that these features are common for a number of inducible and tissue-specific genes [11][12][13][14]. Many myeloid promoters that direct lineage specific expression generally lack a TATA box or defined initiator sequence [15][16][17][18][19].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Mouse Myeloid-associated Differentiation Marker (Myadm) Gene: Promoter Analysis and Protein Localization

2005

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“…In contrast, rat PS-1 is poorly expressed in liver, kidney, lung, and heart (27), and mouse PS-1 is poorly expressed in skeletal muscle and spleen. 2 We also reported that the PS-1 promoter was more active in cells differentiated to become neurons than in cells differentiated to a muscle phenotype (28). These differences suggest both cell type-specific and species-specific distributions of PS-1 expression.…”

mentioning

confidence: 81%

Activated cAMP-response Element-binding Protein Regulates Neuronal Expression of Presenilin-1

Mitsuda

Ohkubo

Tamatani

et al. 2001

Journal of Biological Chemistry

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Alzheimer's disease is a devastating neurological disorder characterized by progressive memory loss and cognitive deficits. To date, four genes have been found to be associated with Alzheimer's disease phenotypes including the amyloid precursor protein gene on chromosome 21 (1-4), the apolipoprotein E gene on chromosome 19 (5-7), the presenilin-1 (PS-1) 1 gene on chromosome 14 (8), and the presenilin-2 (PS-2) gene on chromosome 1 (9, 10). The majority of familial Alzheimer's disease cases are associated with over 40 independent mutations in the PS-1 genes of unrelated families that all display an early-ageof-onset Alzheimer's phenotype (8,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the current literature suggests that intracellular PS-1 is intimately associated with the ␥-secretase activity that facilitates amyloid-␤ peptide release (26), the precise function of PS-1 proteins found in the synaptic membranes remains elusive and is also a matter of active investigation. Human PS-1 is widely expressed in a variety of organs throughout the body (8). This distribution raises the question as to why mutations in the PS-1 gene and its products appear to confer a disease state that selectively affects the brains of patients with familial Alzheimer's disease without apparent effect on their peripheral organs. In contrast, rat PS-1 is poorly expressed in liver, kidney, lung, and heart (27), and mouse PS-1 is poorly expressed in skeletal muscle and spleen. 2 We also reported that the PS-1 promoter was more active in cells differentiated to become neurons than in cells differentiated to a muscle phenotype (28). These differences suggest both cell type-specific and species-specific distributions of PS-1 expression. The brain, however, is the only organ where PS-1 is universally well expressed in human, rat, and mouse species. Using in situ hybridization, PS-1 mRNA is most highly expressed in neurons and below the limit of detection in other brain cells (29,30). These results strongly suggest the existence of a mechanism where PS-1 transcription is regulated in a neuron-specific manner in the brain.To understand presenilin-1 function, one of our approaches is to study regulatory mechanisms in the brain. PS-1 expression is higher in the hippocampus and cerebellum than in the cerebral cortex (29 -32). Hippocampal pyramidal neurons, dentate granule neurons, cerebellar Purkinje neurons, and primary olfactory cortical neurons show higher PS-1 expression than the neurons in other cortical regions of rat brain (33,34). Compared with the adult, the level of PS-1 expression is significantly higher in the developing rat brain. Peaking at postnatal day 10, PS-1 expression in the hippocampus and cerebellum is greatest at a time when proliferation, migration, and synapse formation are actively being completed (35).

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Transcriptional Regulation of the Mouse Presenilin-1 Gene

Cited by 32 publications

References 29 publications

An Upstream Element Containing an ETS Binding Site Is Crucial for Transcription of the Human Presenilin-1 Gene

An Upstream Element Containing an ETS Binding Site Is Crucial for Transcription of the Human Presenilin-1 Gene

Characterization of the Mouse Myeloid-associated Differentiation Marker (Myadm) Gene: Promoter Analysis and Protein Localization

Activated cAMP-response Element-binding Protein Regulates Neuronal Expression of Presenilin-1

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