Presenilin-1 D257A and D385A Mutants Fail to Cleave Notch in Their Endoproteolyzed Forms, but Only Presenilin-1 D385A Mutant Can Restore Its γ-Secretase Activity with the Compensatory Overexpression of Normal C-terminal Fragment

Kim, Hangun; Ki, Hyunkyoung; Park, Hee-Sae; Kim, Kwonseop

doi:10.1074/jbc.m502769200

Cited by 36 publications

(31 citation statements)

References 54 publications

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“…(M146V, S170F, L392V) linked to FAD (11, 24 -27), known to increase the production of A␤42, and with the loss of function mutation D385A (28). PS1 mutations determined a significant elevation of BACE1 mRNA (27-53%), protein levels (172-302%), and activity (81-160%) compared with wild type PS1 expressed at a similar level (Fig.…”

Section: Presenilin 1 Mutations Determine An Increase In Bace1 Activimentioning

confidence: 98%

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Mutant Presenilin 1 Increases the Expression and Activity of BACE1

Giliberto

Borghi

Piccini

et al. 2009

Journal of Biological Chemistry

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Mutations of the presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer disease (FAD). PS1 mutations alter the activity of the ␥-secretase on the ␤-amyloid precursor protein (APP), leading to selective overproduction of ␤-amyloid (A␤) 42 peptides, the species that forms oligomers that may exert toxic effects on neurons. Here we show that PS1 mutations, expressed both transiently and stably, in non-neuronal and neuronal cell lines increase the expression and the activity of the ␤-secretase (BACE1), the rate-limiting step of A␤ production. Also, BACE1 expression and activity are elevated in brains of PS1 mutant knock-in mice compared with wild type littermates as well as in cerebral cortex of FAD cases bearing various PS1 mutations compared with in sporadic AD cases and controls. The up-regulation of BACE1 by PS1 mutations requires the ␥-secretase cleavage of APP and is proportional to the amount of secreted A␤42. A␤42, and not AICD (APP intracellular domain), is indeed the APP derivative that mediates the overexpression of BACE1. The effect of PS1 mutations on BACE1 may contribute to determine the wide clinical and pathological phenotype of early onset FAD.The ␤-amyloid peptide (A␤) 2 that accumulates in vulnerable brain regions in Alzheimer disease (AD) is released from the ␤-amyloid precursor protein (APP) by sequential cleavages by ␤-secretase and ␥-secretase. A single protein called BACE1 is responsible for ␤-secretase activity, whereas ␥-secretase involves at least four proteins including a catalytic subunit called presenilin-1 (PS1) (1, 2). Mutations of PS1 are the most common cause of early onset familial AD (FAD). The known effect of PS1 mutations on APP processing is the increased production of A␤ species ending at residue 42, which aggregates faster than the A␤40 isoform and accumulates in the brain in the state of soluble low molecular weight oligomers (3, 4). Small, soluble, and diffusible aggregates composed of a mixture of full-length and N-terminal-truncated A␤42 species appear early in the cerebral cortex of subjects at risk of Alzheimer disease pathology (5). The rate of accumulation as well as the properties of aggregation and toxicity of cerebral soluble A␤ depend on the ratio of the three major A␤ species, 1-42, pyroglutamate 3-42, and pyroglutamate 11-42 (6). We have shown that, in the cerebral cortex of FAD cases with mutations of PS1, the relative percentage of the two N-terminal-truncated A␤ species is significantly increased in comparison to sporadic AD cases (7). A relative increase of N-terminal-truncated A␤ peptides also occurs in the brain of transgenic mice bearing a double PS1 mutation (8). When overexpressed in cell lines, BACE1 increases the production of A␤ 11-x (9) and A␤ 3-x peptides (10) in vitro. BACE1 has been found to be transcriptionally regulated by several different mechanisms involving various transcription factors and pathways (11)(12)(13)(14)(15), and given the complexity and richness in transcription factor recognition sites of its gene p...

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Section: Presenilin 1 Mutations Determine An Increase In Bace1 Activimentioning

confidence: 98%

“…1, B and E, the PS1 D385A CTF is barely visible, as this mutant undergoes little endoproteolysis (28). Full-length D385A PS1 was detected, ascertaining the efficiency of transfection for this mutant as well (not shown).…”

Section: Presenilin 1 Mutations Determine An Increase In Bace1 Activimentioning

confidence: 99%

Mutant Presenilin 1 Increases the Expression and Activity of BACE1

Giliberto

Borghi

Piccini

et al. 2009

Journal of Biological Chemistry

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“…After proteins were transferred to hydrophobic polyvinylidene difluoride (PVDF) or nitrocellulose membranes (Millipore), Western blots were performed with appropriate antibodies and developed with ECL Western blotting detection reagents (Amersham). Immunoprecipitation was performed as previously described [19].…”

Section: Cell Culture Transfection Immunoprecipitation and Western mentioning

confidence: 99%

Identification of E2F1 as a positive transcriptional regulator for δ-catenin

Kim

et al. 2008

Biochemical and Biophysical Research Communications

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Abstractδ-Catenin is upregulated in human carcinomas. However, little is known about the potential transcriptional factors that regulate δ-catenin expression in cancer. Using a human δ-catenin reporter system, we have screened several nuclear signaling modulators to test whether they can affect δ-catenin transcription. Among β-catenin/LEF-1, Notch1, and E2F1, E2F1 dramatically increased δ-catenin-luciferase activities while β-catenin/LEF-1 induced only a marginal increase. Rb suppressed the upregulation of δ-catenin-luciferase activities induced by E2F1 but did not interact with δ-catenin. RT-PCR and Western blot analyses in 4 different prostate cancer cell lines revealed that regulation of δ-catenin expression is controlled mainly at the transcriptional level. Interestingly, the effects of E2F1 on δ-catenin expression were observed only in human cancer cells expressing abundant endogenous δ-catenin. These studies identify E2F1 as a positive transcriptional regulator for δ-catenin, but further suggest the presence of strong negative regulator(s) for δ-catenin in prostate cancer cells with minimal endogenous δ-catenin expression.

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“…Immunoblotting and Akt Kinase Assay-Immunoprecipitation/immunoblotting was performed as previously described (39). For the kinase assays, the full-length and mutant GFP-␦-catenin constructs were transiently overexpressed in MEF cells or Bosc23 cells.…”

Section: Methodsmentioning

confidence: 99%

δ-Catenin-induced Dendritic Morphogenesis

Kim

Han

Park

et al. 2008

Journal of Biological Chemistry

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␦-Catenin was first identified through its interaction withPresenilin-1 and has been implicated in the regulation of dendrogenesis and cognitive function. However, the molecular mechanisms by which ␦-catenin promotes dendritic morphogenesis were unclear. In this study, we demonstrated ␦-catenin interaction with p190RhoGEF, and the importance of Akt1-mediated phosphorylation at Thr-454 residue of ␦-catenin in this interaction. We have also found that ␦-catenin overexpression decreased the binding between p190RhoGEF and RhoA, and significantly lowered the levels of GTP-RhoA but not those of GTP-Rac1 and -Cdc42. ␦-Catenin T454A, a defective form in p190RhoGEF binding, did not decrease the binding between p190RhoGEF and RhoA. ␦-Catenin T454A also did not lower GTP-RhoA levels and failed to induce dendrite-like process formation in NIH 3T3 fibroblasts. Furthermore, ␦-catenin T454A significantly reduced the length and number of mature mushroom shaped spines in primary hippocampal neurons. These results highlight signaling events in the regulation of ␦-catenininduced dendrogenesis and spine morphogenesis.␦-Catenin was first identified by yeast two-hybrid screening as a molecule that interacts with Presenilin-1 (PS-1), 3 which is the most prominently mutated gene in familial Alzheimer disease (FAD) patients (1, 2). The interaction of ␦-catenin with PS-1, along with its abundant expression in neurons, suggests that ␦-catenin has specialized neuronal functions (3, 4). Indeed, ␦-catenin-deficient mice showed severe learning deficits and abnormal synaptic plasticity, suggesting a special role of ␦-catenin at the synapse (5). Furthermore, the hemizygous loss of the chromosomal 5p15.2 region, which contains the human ␦-catenin gene, results in the severe mental retardation associated with Cri du Chat syndrome. This chromosomal abnormality may account for 1% of all mentally retarded individuals (6).Structural analysis indicated that ␦-catenin is a member of the p120-Catenin (hereafter, p120 ctn ) subfamily of armadillo proteins and has a DSWV sequence at the C terminus that binds to the PDZ (PSD-95/Disc-larg/ZO-1) domain-containing proteins (7). ␦-Catenin also contains SH3 binding domains at the N terminus (4, 8), a GKKKKKKK sequence (putative NLS) that can potentially promote lipid intermixing (9), and a proline-rich domain that is likely to be involved in the interaction with the actin-binding protein, Profilin (4). The presence of 10 Arm repeats in ␦-catenin suggests its potential participation in various protein-protein interactions. In addition to PS-1, the ␦-catenin-associated proteins identified thus far include E-cadherin (4), S-SCAM (7), p0071 (10), Densin-180 (11), PSD-95, Abl (8), Cortactin (12), sphingosine kinase (13), and Kaiso (14), suggesting its many possible roles in cells. Our previous reports demonstrated that the overexpression of ␦-catenin induces the branching of dendrite-like processes in both NIH 3T3 fibroblasts and primary hippocampal neurons (15). We have also reported that an E18 hippocampal neuron ...

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Presenilin-1 D257A and D385A Mutants Fail to Cleave Notch in Their Endoproteolyzed Forms, but Only Presenilin-1 D385A Mutant Can Restore Its γ-Secretase Activity with the Compensatory Overexpression of Normal C-terminal Fragment

Cited by 36 publications

References 54 publications

Mutant Presenilin 1 Increases the Expression and Activity of BACE1

Mutant Presenilin 1 Increases the Expression and Activity of BACE1

Identification of E2F1 as a positive transcriptional regulator for δ-catenin

δ-Catenin-induced Dendritic Morphogenesis

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