Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis

Liang, Cyong-Jhih; Chang, Yaw-Jen; Chang, Henry; Wang, Chung-Kang; Hung, Yu‐Chien; Lin, Ying-Er; Chan, Chia-Ching; Chen, Chun Hong; Chang, Hui-Yun; Sang, Tzu-Kang

doi:10.1371/journal.pgen.1004675

Cited by 21 publications

(28 citation statements)

References 59 publications

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“…The family of Der1 proteins has emerged as a vital component of the ERAD pathway [15]. DERL1 is a partner of the p97 ATPase complex and plays a key role in the mislocalization of the misfolded protein; it also integrates into the endoplasmic reticulum (ER) membrane to survey such protein aggregates [16, 17].…”

Section: Introductionmentioning

confidence: 99%

MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

Yang

Wei

Qin

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs regulate a wide range of biological processes of non-small cell lung cancer (NSCLC). Although miR-598 has been reported to act as a suppressor in osteosarcoma and colorectal cancer, the physiological function of miR-598 in NSCLC remains unknown. In this study, the role of miR-598 in NSCLC was investigated. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to estimate the expression of miR-598 and Derlin-1 (DERL1) in both NSCLC tissues and cell lines. Immunohistochemistry (IHC) analyzed the association between the miR-598 expression and epithelial-mesenchymal transition (EMT) hallmark genes (E-cadherin, Vimentin) by staining the tumors representative of the high- and low-expression groups. The effect of miR-598 and DERL1 on invasion and migration was determined in vitro using transwell and wound-healing assays. The molecular mechanism underlying the relevance between miR-598 and DERL1 was elucidated by luciferase assay and Western blot. Western blot assessed the expression levels of EMT hallmark genes in cell lines. Xenograft tumor formation assay was conducted as an in vivo experiment. Results: In this study, a relatively low level of miR-598 and high DERL1 expressions were found in NSCLC specimens and cell lines. IHC results established a positive correlation between the miR-598 expression and E-cadherin and a negative with Vimentin. DERL1 was verified as a direct target of miR-598 by luciferase assay. In vitro, the over-expression of miR-598 negatively regulated DERL1 and EMT for the suppression of invasion and migration. In vivo, the over-expression of miR-598 could inhibit tumor cell metastasis in NSCLC. Conclusions: These findings for the first time revealed that miR-598, as a tumor suppressor, negatively regulate DERL1 and EMT to suppress the invasion and migration in NSCLC, thereby putatively serving as a novel therapeutic target for NSCLC clinical treatment.

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Section: Introductionmentioning

confidence: 99%

MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

Yang

Wei

Qin

et al. 2018

Cell Physiol Biochem

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“…As the molecular function of VCP has been extensively studied, we suspect that the enlarged nuclei defect may be linked to one of its characterized roles. We have previously shown that overexpression of Derlin-1, a direct interactor of TER94, retains TER94 in the cytoplasm 30 respectively suggests a similar mechanism may exist in Drosophila. In support of this, MDC1 is known to interact with p53 via the BRCT domain 37,38 , which is conserved in Drosophila Mu2 .…”

Section: Discussionmentioning

confidence: 93%

“…As a control, expression of Derlin-1 ΔSHP , a Derlin-1 construct incapable of binding to TER94 30 , had no effect on the nuclear TER94 level and the nuclear size (Fig. 3a, b).…”

Section: Disruption Of Nuclear Ter94 Function In Dna Damage Repair Afmentioning

confidence: 99%

“…Given the correlation between ubiquitinated protein accumulation in the nucleus and the nuclear size expansion, we speculated these defects were due to a deficit of TER94 function in the nucleus. To test this hypothesis, we took advantage of a fortuitous finding of ours that overexpression of Derlin-1, an ER membrane protein that recruits TER94 to the ER vicinity upon ER stress, depletes the nuclear pool of endogenous TER94 30 (Fig. 3a, b).…”

Section: Disruption Of Nuclear Ter94 Function In Dna Damage Repair Afmentioning

confidence: 99%

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VCP functions to maintain nuclear size by managing DNA damage-induced MDC1–p53–autophagy axis

Chang

Peng

Shih

et al. 2020

Preprint

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Anomalies in nuclear morphology have been linked to aging-related diseases and malignant transformation, although the mechanism responsible for this connection remains unclear. By expressing dominant-negative TER94 (TER94K2A) mutants in Drosophila photoreceptors, we show disruption of VCP (valosin-containing protein, TER94 ortholog in human), an AAA (ATPase associated with various cellular activities) ATPase essential for ubiquitin-dependent segregation or degradation of proteins, causes an age-dependent nuclear size increase. Loss of VCP function leads to accumulations of MDC1 (mediator of DNA damage checkpoint protein 1), a key DNA damage response gene, and increased γH2AV (an indicator of DNA damage), linking excessive DNA damages and associated responses to this enlarged nuclei defect. Indeed, MDC1-overexpression, similar to TER94K2A, increases γH2AV staining and nuclear size. Moreover, TER94 negatively influences MDC1 level and could interact with MDC1, suggesting that MDC1 is a VCP substrate. MDC1 accumulation increases p53 stability, and this VCP-MDC1-p53 connection is functional, as removal of p53 function suppresses the ability of TER94K2A and MDC1 overexpression to increase nuclear size. While p53 is capable of generating multiple isoforms, our genetic evidence suggests that the p53A isoform specifically contributes to this TER94K2A-associated nuclear size increase. Combining our results with a previous report that p53A expression disrupts autophagic flux, we propose that the failure of removing MDC1 in TER94K2A-expressing cells stabilizes p53A, which blocks autophagy and likely hinders the removal of nuclear content, resulting in aberrant nuclear size increase.

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“…Increasing evidence has shown that Derlin1 is overexpressed in most kind of cancer, including cervical cancer and the expression of Derlin1 is closely related to the occurrence and development of tumors. (Liang et al, 2014;Yang et al, 2018). Derlin1 knockdown inhibited cell migration in a bladder cancer cell model .…”

Section: Introductionmentioning

confidence: 98%

Functionalized selenium nanoparticles for targeted siRNA delivery silence Derlin1 and promote antitumor efficacy against cervical cancer

et al. 2019

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2020) Functionalized selenium nanoparticles for targeted siRNA delivery silence Derlin1 and promote antitumor efficacy against cervical cancer, Drug Delivery, 27:1, 15-25, ABSTRACT Small interfering RNA (siRNA) exhibits great potential as a novel therapeutic option due to its highly sequence-specific ability to silence genes. However, efficient and safe delivery carriers are required for developing novel therapeutic paradigms. Thus, the successful development of efficient delivery platforms for siRNA is a crucial issue for the development of siRNA-based drugs in cancer treatments. In this study, biocompatible selenium nanoparticles (SeNPs) were loaded with RGDfC peptide to fabricate tumor-targeting gene delivery vehicle RGDfC-SeNPs. Subsequently, RGDfC-SeNPs were loaded with Derlin1-siRNA to fabricate RGDfC-Se@siRNA, which are functionalized selenium nanoparticles. RGDfC-Se@siRNA showed greater uptake in HeLa cervical cancer cells in comparison with that in human umbilical vein endothelial cells (HUVECs), verifying the RGDfC-mediated specific uptake of RGDfC-Se@siRNA. RGDfC-Se@siRNA was capable of entering HeLa cells via clathrin-associated endocytosis, and showed faster siRNA release in a cancer cell microenvironment in comparison with a normal physiological environment. qPCR and western blotting assays both indicated that RGDfC-Se@siRNA exhibited an obvious gene silencing efficacy in HeLa cells. RGDfC-Se@siRNA suppressed the invasion, migration and the proliferation of HeLa cells, and triggered HeLa cell apoptosis. Moreover, RGDfC-Se@siRNA induced the disruption of mitochondrial membrane potentials. Meanwhile, RGDfC-Se@siRNA enhanced the generation of reactive oxygen species (ROS) in HeLa cell, suggesting that mitochondrial dysfunction mediated by ROS might play a significant role in RGDfC-Se@siRNA-induced apoptosis. Interestingly, RGDfC-SeNPs@siRNA exhibited significant antitumor activity in a HeLa tumor-bearing mouse model. Additionally, RGDfC-SeNPs@siRNA is nontoxic to main organ of mouse. The above results indicate that RGDfC-Se@siRNA provides a promising potential for cervical cancer therapy. ARTICLE HISTORY

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Derlin-1 Regulates Mutant VCP-Linked Pathogenesis and Endoplasmic Reticulum Stress-Induced Apoptosis

Cited by 21 publications

References 59 publications

MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

VCP functions to maintain nuclear size by managing DNA damage-induced MDC1–p53–autophagy axis

Functionalized selenium nanoparticles for targeted siRNA delivery silence Derlin1 and promote antitumor efficacy against cervical cancer

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