Expression of metalloprotease insulin-degrading enzyme insulysin in normal and malignant human tissues

Yfanti, Christina; Mengele, Karin; Gkazepis, Apostolos; Weirich, Gregor; Giersig, C.; Kuo, Wen-Liang; Tang, Wei-Jen; Rosner, Marsha Rich

doi:10.3892/ijmm_00000038

Cited by 8 publications

(1 citation statement)

References 50 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…840301, San Diego, CA) and was formerly available from Covance as product no. PRB-282C (87). Anti-GAPDH antibody (6C5) and horseradish peroxidase (HRP)-conjugated secondary antibodies were purchased from Santa Cruz Technologies (Santa Cruz, CA).…”

Section: Introductionmentioning

confidence: 99%

Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues

Kulas

Franklin

Smith

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

The amyloid precursor protein (APP) is a type I transmembrane glycoprotein widely studied for its role as the source of β-amyloid peptide, accumulation of which is causal in at least some cases of Alzheimer’s disease (AD). APP is expressed ubiquitously and is involved in diverse biological processes. Growing bodies of evidence indicate connections between AD and somatic metabolic disorders related to type 2 diabetes, and App−/− mice show alterations in glycemic regulation. We find that App−/− mice have higher levels of insulin-degrading enzyme (IDE) mRNA, protein, and activity compared with wild-type controls. This regulation of IDE by APP was widespread across numerous tissues, including liver, skeletal muscle, and brain as well as cell types within neural tissue, including neurons, astrocytes, and microglia. RNA interference-mediated knockdown of APP in the SIM-A9 microglia cell line elevated IDE levels. Fasting levels of blood insulin were lower in App−/− than App+/+ mice, but the former showed a larger increase in response to glucose. These low basal levels may enhance peripheral insulin sensitivity, as App−/− mice failed to develop impairment of glucose tolerance on a high-fat, high-sucrose (“Western”) diet. Insulin levels and insulin signaling were also lower in the App−/− brain; synaptosomes prepared from App−/− hippocampus showed diminished insulin receptor phosphorylation compared with App+/+ mice when stimulated ex vivo. These findings represent a new molecular link connecting APP to metabolic homeostasis and demonstrate a novel role for APP as an upstream regulator of IDE in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues

Kulas

Franklin

Smith

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S

Sbardella

Tundo

Coletta

et al. 2018

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE) ≤ 30 nM and activating at (IDE) ≥ 30 nM. Only an activating effect is observed in a yeast mutant locked in the "open" conformation (i.e., the α-3ΔN 20S), envisaging a possible role of IDE as modulator of the 20S "open"-"closed" allosteric equilibrium. Protein-protein docking in silico proposes that the interaction between IDE and the 20S could involve the C-term helix of the 20S α-3 subunit which regulates the gate opening of the 20S.

show abstract

Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals

Pacis

et al. 2017

Transl Psychiatry

View full text Add to dashboard Cite

5-Hydroxymethylcytosine (5hmC) is a recently characterized epigenetic mark that is particularly abundant in brain tissue and that regulates gene transcription. We have recently begun to understand the important role of 5hmC in brain development, plasticity and disease, but there are currently little data on 5hmC alterations in psychiatric illnesses. Here we report what we believe to be the first genome-wide analysis of 5hmC in the depressed brain. Using AbaSI sequencing, we investigated 5hmC in the prefrontal cortex of depressed (N=19) and psychiatrically healthy controls (N=19). Consistent with previous global 5hmC analyses in other phenotypes, and likely owing to the inter-individual variability in 5hmC content, the distribution of 5hmC across chromosomes and genomic features was not different between groups. We did, however, find 550 CpGs with suggestive evidence of differential hydroxymethylation. Of these, we validated CpGs in the gene body of myosin XVI (MYO16) and insulin-degrading enzyme using targeted oxidative bisulfite sequencing. Furthermore, the enrichment of 5hmC was also associated with changes in the expression of these two genes in depressed suicides. Together, our results present a novel mechanism linking increased 5hmC to depression and provide a framework for future research in this field.

show abstract

Expression of metalloprotease insulin-degrading enzyme insulysin in normal and malignant human tissues

Cited by 8 publications

References 50 publications

Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues

Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues

The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S

Gene-body 5-hydroxymethylation is associated with gene expression changes in the prefrontal cortex of depressed individuals

Contact Info

Product

Resources

About