Swedish amyloid precursor protein mutation increases cell cycle-related proteins in vitro and in vivo

2008 ◽  
Vol 86 (11) ◽  
pp. 2476-2487 ◽  
Author(s):  
Kwang-Woo Ahn ◽  
Yuyoung Joo ◽  
Yoori Choi ◽  
Minji Kim ◽  
Sang Hyoung Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Protein Mutation ◽  
Amyloid Precursor Protein Mutation ◽  
Related Proteins

P3-311: Swedish amyloid precursor protein mutation increases cell cycle-related proteins in vitro and in vivo

2008 ◽  
Vol 4 ◽  
pp. T613-T613
Author(s):  
Yoori Choi ◽  
Kwang-Woo Ahn ◽  
Yuyoung Joo ◽  
Minji Kim ◽  
Sang Hyoung Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Protein Mutation ◽  
Amyloid Precursor Protein Mutation ◽  
Related Proteins

Swedish amyloid precursor protein mutation increases phosphorylation of eIF2α in vitro and in vivo

2007 ◽  
Vol 85 (7) ◽  
pp. 1528-1537 ◽  
Author(s):  
Hye-Sun Kim ◽  
Yoori Choi ◽  
Ki-Young Shin ◽  
Yuyoung Joo ◽  
Yong-Kyu Lee ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Protein Mutation ◽  
Amyloid Precursor Protein Mutation

scholarly journals Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

2016 ◽  
Vol 291 (33) ◽  
pp. 17209-17227 ◽  
Author(s):  
Dolores Del Prete ◽  
Richard C. Rice ◽  
Anjali M. Rajadhyaksha ◽  
Luciano D'Adamio
Keyword(s):  
Amyloid Precursor Protein ◽  
Transmitter Release ◽  
Ubiquitin Proteasome System ◽  
Precursor Protein ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Functional Pathway ◽  
Related Proteins

The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4CRBN, which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn. APP shares essential functions with APP-like protein-2 (APLP2) but not APP-like protein-1 (APLP1). Noteworthy, APLP2, but not APLP1, interacts with Stub1 and CRL4CRBN, pointing to a functional pathway shared only by APP and APLP2. In vitro ubiquitination/ubiquitome analysis indicates that these E3 ligases are enzymatically active and ubiquitinate the ACR residues Lys649/650/651/676/688. Deletion of Crbn reduces ubiquitination of Lys676 suggesting that Lys676 is physiologically ubiquitinated by CRL4CRBN. The ACR facilitated in vitro ubiquitination of presynaptic proteins that regulate exocytosis, suggesting a mechanism by which APP tunes transmitter release. Other dementia-related proteins, namely Tau and apoE, interact with and are ubiquitinated via the ACR in vitro. This, and the evidence that CRBN and CUL4B are linked to intellectual disability, prompts us to hypothesize a pathogenic mechanism, in which APP acts as a modulator of E3 ubiquitin-protein ligase(s), shared by distinct neuronal disorders. The well described accumulation of ubiquitinated protein inclusions in neurodegenerative diseases and the link between the ubiquitin-proteasome system and neurodegeneration make this concept plausible.

scholarly journals The inhibitory effect of silencing CDCA3 on migration and proliferation in bladder urothelial carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dexin Shen ◽  
Yayun Fang ◽  
Fenfang Zhou ◽  
Zhao Deng ◽  
Kaiyu Qian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Urothelial Carcinoma ◽  
Carcinoma Cells ◽  
Expression Level ◽  
Tumor Cell Growth ◽  
Migration Ability ◽  
Bladder Urothelial Carcinoma ◽  
Related Proteins

Abstract Background CDCA3 is an important component of the E3 ligase complex with SKP1 and CUL1, which could regulate the progress of cell mitosis. CDCA3 has been widely identified as a proto-oncogene in multiple human cancers, however, its role in promoting human bladder urothelial carcinoma has not been fully elucidated. Methods Bioinformatic methods were used to analyze the expression level of CDCA3 in human bladder urothelial carcinoma tissues and the relationship between its expression level and key clinical characteristics. In vitro studies were performed to validate the specific functions of CDCA3 in regulating cell proliferation, cell migration and cell cycle process. Alterations of related proteins was investigated by western blot assays. In vivo studies were constructed to validate whether silencing CDCA3 could inhibit the proliferation rate in mice model. Results Bioinformatic analysis revealed that CDCA3 was significantly up-regulated in bladder urothelial carcinoma samples and was related to key clinical characteristics, such as tumor grade and metastasis. Moreover, patients who had higher expression level of CDCA3 tend to show a shorter life span. In vitro studies revealed that silencing CDCA3 could impair the migration ability of tumor cells via down-regulating EMT-related proteins such as MMP9 and Vimentin and inhibit tumor cell growth via arresting cells in the G1 cell cycle phase through regulating cell cycle related proteins like p21. In vivo study confirmed that silencing CDCA3 could inhibit the proliferation of bladder urothelial carcinoma cells. Conclusions CDCA3 is an important oncogene that could strengthen the migration ability of bladder urothelial carcinoma cells and accelerate tumor cell growth via regulating cell cycle progress and is a potential biomarker of bladder urothelial carcinoma.

scholarly journals Nitrous Oxide Plus Isoflurane Induces Apoptosis and Increases β-Amyloid Protein Levels

2009 ◽  
Vol 111 (4) ◽  
pp. 741-752 ◽  
Author(s):  
Yu Zhen ◽  
Yuanlin Dong ◽  
Xu Wu ◽  
Zhipeng Xu ◽  
Yan Lu ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Amyloid Precursor Protein ◽  
Caspase 3 ◽  
Precursor Protein ◽  
Primary Neurons ◽  
Gamma Secretase ◽  
Protein Levels ◽  
Secretase Inhibitor

Background Some anesthetics have been suggested to induce neurotoxicity, including promotion of Alzheimer's disease neuropathogenesis. Nitrous oxide and isoflurane are common anesthetics. The authors set out to assess the effects of nitrous oxide and/or isoflurane on apoptosis and beta-amyloid (Abeta) levels in H4 human neuroglioma cells and primary neurons from naïve mice. Methods The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for 6 h. The cells or neurons and conditioned media were harvested at the end of the treatment. Caspase-3 activation, apoptosis, processing of amyloid precursor protein, and Abeta levels were determined. Results Treatment with a combination of 70% nitrous oxide and 1% isoflurane for 6 h induced caspase-3 activation and apoptosis in H4 naïve cells and primary neurons from naïve mice. The 70% nitrous oxide plus 1% isoflurane, but neither alone, for 6 h induced caspase-3 activation and apoptosis, and increased levels of beta-site amyloid precursor protein-cleaving enzyme and Abeta in H4-amyloid precursor protein cells. In addition, the nitrous oxide plus isoflurane-induced Abeta generation was reduced by a broad caspase inhibitor, Z-VAD. Finally, the nitrous oxide plus isoflurane-induced caspase-3 activation was attenuated by gamma-secretase inhibitor L-685,458, but potentiated by exogenously added Abeta. Conclusion These results suggest that the common anesthetics nitrous oxide plus isoflurane may promote neurotoxicity by inducing apoptosis and increasing Abeta levels. The generated Abeta may further potentiate apoptosis to form another round of apoptosis and Abeta generation. More studies, especially the in vivo confirmation of these in vitro findings, are needed.

scholarly journals SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1275
Author(s):  
Soo Yong Park ◽  
Joo Yeong Kang ◽  
Taehee Lee ◽  
Donggyu Nam ◽  
Chang-Jin Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Physiological Activity ◽  
Precursor Protein ◽  
Age Related

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

scholarly journals Presenilin 1 Controls γ-Secretase Processing of Amyloid Precursor Protein in Pre-Golgi Compartments of Hippocampal Neurons

1999 ◽  
Vol 147 (2) ◽  
pp. 277-294 ◽  
Author(s):  
Wim G. Annaert ◽  
Lyne Levesque ◽  
Kathleen Craessaerts ◽  
Inge Dierinck ◽  
Greet Snellings ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Amyloid Precursor Protein ◽  
Hippocampal Neurons ◽  
Subcellular Fractionation ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Carboxy Terminal ◽  
Endocytic Pathways

Mutations of presenilin 1 (PS1) causing Alzheimer's disease selectively increase the secretion of the amyloidogenic βA4(1-42), whereas knocking out the gene results in decreased production of both βA4(1-40) and (1-42) amyloid peptides (De Strooper et al. 1998). Therefore, PS1 function is closely linked to the γ-secretase processing of the amyloid precursor protein (APP). Given the ongoing controversy on the subcellular localization of PS1, it remains unclear at what level of the secretory and endocytic pathways PS1 exerts its activity on APP and on the APP carboxy-terminal fragments that are the direct substrates for γ-secretase. Therefore, we have reinvestigated the subcellular localization of endogenously expressed PS1 in neurons in vitro and in vivo using confocal microscopy and fine-tuned subcellular fractionation. We show that uncleaved PS1 holoprotein is recovered in the nuclear envelope fraction, whereas the cleaved PS fragments are found mainly in post-ER membranes including the intermediate compartment (IC). PS1 is concentrated in discrete sec23p- and p58/ERGIC-53–positive patches, suggesting its localization in subdomains involved in ER export. PS1 is not found to significant amounts beyond the cis-Golgi. Surprisingly, we found that APP carboxy-terminal fragments also coenrich in the pre-Golgi membrane fractions, consistent with the idea that these fragments are the real substrates for γ-secretase. Functional evidence that PS1 exerts its effects on γ-secretase processing of APP in the ER/IC was obtained using a series of APP trafficking mutants. These mutants were investigated in hippocampal neurons derived from transgenic mice expressing PS1wt or PS1 containing clinical mutations (PS1M146L and PS1L286V) at physiologically relevant levels. We demonstrate that the APP-London and PS1 mutations have additive effects on the increased secretion of βA4(1-42) relative to βA4(1-40), indicating that both mutations operate independently. Overall, our data clearly establish that PS1 controls γ42-secretase activity in pre-Golgi compartments. We discuss models that reconcile this conclusion with the effects of PS1 deficiency on the generation of βA4(1-40) peptide in the late biosynthetic and endocytic pathways.

Nerve growth factor does not influence the expression of β amyloid precursor protein mRNA in rat brain: in vivo and in vitro studies

1993 ◽  
Vol 620 (2) ◽  
pp. 292-296 ◽  
Author(s):  
Gianluigi Forloni ◽  
Roberto Del Bo ◽  
Nadia Angeretti ◽  
Simona Smiroldo ◽  
Nadia Gabellini ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Amyloid Precursor Protein ◽  
Rat Brain ◽  
Precursor Protein ◽  
In Vitro Studies ◽  
Nerve Growth ◽  
Β Amyloid
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