Putative alternative functions of human stefin B (cystatin B): binding to amyloid‐beta, membranes, and copper

Žerovnik, Eva

doi:10.1002/jmr.2562

Cited by 20 publications

(13 citation statements)

References 85 publications

(134 reference statements)

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“…Cystatin B (CSTB, stefin B) is an endogenous inhibitor of intracellular cysteine proteases (1,2). Previously, we reported that CSTB is a progression marker of human epithelial ovarian cancer (OC) (3), a disease ranked as the eight most common cancer worldwide in females (4) and gynecological cancer with the highest rate of mortality in the United States of America (5).…”

Section: Introductionmentioning

confidence: 99%

“…After the Smad-complex translocates into the nucleus, it acts as a transcription factor to regulate the expression of a target gene (21). Smad-independent Transforming growth factor-β/miR-143-3p/cystatin B axis is a therapeutic target in human ovarian cancer WENCAI GUAN 1 , XINGXING WANG 1 , QUNBO LIN 1 , JINGUO ZHANG 1,2 , WEIMIN REN 1,2 and GUOXIONG XU 1,2 pathways, such as the MAPK and PI3K signaling pathways, can also be induced by TGF-β to initiate signal transduction and gene regulation (23). The Smad-dependent and -independent pathways have been demonstrated to contribute to the pathogenesis of OC (24,25).…”

Section: Introductionmentioning

confidence: 99%

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Transforming growth factor‑β/miR‑143‑3p/cystatin B axis is a therapeutic target in human ovarian cancer

et al. 2019

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We previously reported that cystatin B (CSTB) is a progression marker of human ovarian cancer (OC); however, the regulatory mechanism of CSTB and its function in OC remain unclear. The present study aimed to explore the mechanism underlying transforming growth factor-β (TGF-β) 1-mediated CSTB regulation, and to examine the function of CSTB on OC cell proliferation and apoptosis. Using the online program, miRWalk, a microRNA (miR)-143-3p was detected, which contains a homologous sequence of the potential binding site to the 3'-untranslated region (3'-UTR) of CSTB. A dual-luciferase reporter assay confirmed the interaction between miR-143-3p and CSTB 3'-UTR. Treating OC cells with miR-143-3p mimics or inhibitors resulted in a decrease or an increase of CSTB expression at mRNA and protein levels, respectively. Additionally, CSTB was significantly overexpressed, whereas miR-143-3p was downregulated in human OC tissues compared with normal ovarian tissues. A negative correlation between miR-143-3p and CSTB mRNA expression was observed in ovarian malignant tumors. The levels of primary and mature miR-143-3p expression were upregulated in OC cells after TGF-β1 treatment; the action of TGF-β1 was abolished in the presence of an inhibitor of TGF-β type I receptor. These results indicated an axis between TGF-β, miR-143-3p and CSTB in OC cells. Furthermore, high levels of CSTB expression were associated with the poor overall survival of patients with OC. Knockdown of CSTB resulted in a decrease in OC cell proliferation and arrested cells in G2/M phase. In addition, suppression of CSTB induced cell apoptosis. In conclusion, CSTB was overexpressed and miR-143-3p was downregulated in ovarian malignant tumors. Mature miR-143-3p directly bound CSTB 3'-UTR, leading to a decrease in CSTB expression in OC cells, which was regulated by TGF-β1. Our findings suggest the potential therapeutic application of targeting the TGF-β/miR-143-3p/CSTB axis for treating patients with OC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transforming growth factor‑β/miR‑143‑3p/cystatin B axis is a therapeutic target in human ovarian cancer

et al. 2019

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“…Currently, several types of inhibitors that target amyloid aggregation are under development, including small molecule inhibitors, peptides, nanoparticles, antibodies, and proteins . Among them, peptides and peptidomimetics have been extensively studied for their specific interactions with Aβ .…”

Section: Introductionmentioning

confidence: 99%

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Zhang

Dong

et al. 2018

J of Molecular Recognition

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Dysfunctional accumulation of amyloid β-protein (Aβ) mediated by Cu exhibits higher neurotoxicity and accelerates the progress of Alzheimer's disease, so inhibition of Cu -mediated Aβ aggregation and cytotoxicity has been considered as a therapeutic strategy for the disease. Herein, a nonapeptide was designed by linking HH to the C-terminus of a peptide inhibitor of Aβ aggregation, LVFFARK (LK7). We found that the nonapeptide, LK7-HH, possessed dual functionality, including enhanced inhibition capability on Aβ aggregation as compared to LK7, and chelating Cu with a dissociation constant of 5.50 μM. This enabled LK7-HH to arrest the generation of reactive oxygen species catalyzed by Cu or Cu -Aβ complex, and to inhibit Cu -induced Aβ aggregation. Moreover, in contrast with the cytotoxicity of LK7 aggregates, LK7-HH was biocompatible because HH conjugation made its aggregation behavior different from LK7. Thus, LK7-HH efficiently suppressed Cu -mediated Aβ aggregation and cytotoxicity. An equimolar concentration of LK7-HH increased cell viability from 50% to 90% when treating Aβ -Cu complexes. The results provided insights into the roles of HH in enhancing the inhibition of Aβ and Cu -induced Aβ aggregations, in eliminating Cu -induced cytotoxicities by arresting generation of reactive oxygen species, and in making the peptide biocompatible. Therefore, this work would contribute to the design of potent peptide-based inhibitors of Cu -mediated Aβ aggregation and cytotoxicity.

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“…Similarly to cystatin C, stefin B protects neurons from excessive oxidative stress [30,31] and protein misfolding [32]. Alternative functions, such as amateur chaperone function, have also been suggested from both experimental data and bioinformatic analysis [33]. A breakthrough in the understanding of the structure of cystatins and their mechanism of interaction with papain-like cysteine proteases, including lysosomal cathepsins, was provided by the three-dimensional (3D) structures of chicken cystatin monomer [34,35] and human stefin B-papain complex [36].…”

Section: Introductionmentioning

confidence: 99%

Proline Residues as Switches in Conformational Changes Leading to Amyloid Fibril Formation

Taler‐Verčič

Hasanbašić

Berbić

et al. 2017

IJMS

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Here we discuss studies of the structure, folding, oligomerization and amyloid fibril formation of several proline mutants of human stefin B, which is a protein inhibitor of lysosomal cysteine cathepsins and a member of the cystatin family. The structurally important prolines in stefin B are responsible for the slow folding phases and facilitate domain swapping (Pro 74) and loop swapping (Pro 79). Moreover, our findings are compared to β2-microglobulin, a protein involved in dialysis-related amyloidosis. The assessment of the contribution of proline residues to the process of amyloid fibril formation may shed new light on the critical molecular events involved in conformational disorders.

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Putative alternative functions of human stefin B (cystatin B): binding to amyloid‐beta, membranes, and copper

Cited by 20 publications

References 85 publications

Transforming growth factor‑β/miR‑143‑3p/cystatin B axis is a therapeutic target in human ovarian cancer

Transforming growth factor‑β/miR‑143‑3p/cystatin B axis is a therapeutic target in human ovarian cancer

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Proline Residues as Switches in Conformational Changes Leading to Amyloid Fibril Formation

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Putative alternative functions of human stefin B (cystatin B): binding to amyloid‐beta, membranes, and copper

Cited by 20 publications

References 85 publications

Transforming growth factor‑β/miR‑143‑3p/cystatin B axis is a therapeutic target in human ovarian cancer

Transforming growth factor‑β/miR‑143‑3p/cystatin B axis is a therapeutic target in human ovarian cancer

Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu2+‐mediated amyloid β‐protein aggregation and cytotoxicity

Proline Residues as Switches in Conformational Changes Leading to Amyloid Fibril Formation

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Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity