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P97 VCP

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https://www.readbyqxmd.com/read/28423563/regulation-of-p53wt-glioma-cell-proliferation-by-androgen-receptor-mediated-inhibition-of-small-vcp-p97-interacting-protein-expression
#1
Dejun Bao, Chuandong Cheng, Xiaoqiang Lan, Rong Xing, Zhuo Chen, Hua Zhao, Junyan Sun, Yang Wang, Chaoshi Niu, Bo Zhang, Shengyun Fang
The incidence of glioma in men is higher than that in women; however, little is known about the expression and basic function of the androgen receptor (AR) in gliomas. AR inhibited the small VCP/p97-interacting protein (SVIP) on the transcriptional level was previously reported. The present study shows that the protein level of AR is highly expressed in cell lines of the nervous system. Moreover, the AR expression is increased while SVIP expression is decreased in tumor tissue of glioma patients, which is in agreement with the progressing WHO grades...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28396624/granulostasis-protein-quality-control-of-rnp-granules
#2
REVIEW
Simon Alberti, Daniel Mateju, Laura Mediani, Serena Carra
Ribonucleoprotein (RNP) granules transport, store, or degrade messenger RNAs, thereby indirectly regulating protein synthesis. Normally, RNP granules are highly dynamic compartments. However, because of aging or severe environmental stress, RNP granules, in particular stress granules (SGs), convert into solid, aggregate-like inclusions. There is increasing evidence that such RNA-protein inclusions are associated with several age-related neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer's disease (AD)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28322724/valosin-containing-protein-vcp-p97-inhibitors-relieve-mitofusin-dependent-mitochondrial-defects-due-to-vcp-disease-mutants
#3
Ting Zhang, Prashant Mishra, Bruce A Hay, David Chan, Ming Guo
Missense mutations of valosin-containing protein (VCP) cause an autosomal dominant disease known as inclusion body myopathy, Paget disease with frontotemporal dementia (IBMPFD) and other neurodegenerative disorders. The pathological mechanism of IBMPFD is not clear and there is no treatment. We show that endogenous VCP negatively regulates Mitofusin, which is required for outer mitochondrial membrane fusion. Because 90% of IBMPFD patients have myopathy, we generated an in vivo IBMPFD model in adult Drosophila muscle, which recapitulates disease pathologies...
March 21, 2017: ELife
https://www.readbyqxmd.com/read/28322292/a-structure-and-chemical-genomics-based-approach-for-repositioning-of-drugs-against-vcp-p97-atpase
#4
Aldo Segura-Cabrera, Reshmi Tripathi, Xiaoyi Zhang, Lin Gui, Tsui-Fen Chou, Kakajan Komurov
Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28320958/p97-vcp-promotes-degradation-of-crbn-substrate-glutamine-synthetase-and-neosubstrates
#5
Thang Van Nguyen, Jing Li, Chin-Chun Jean Lu, Jennifer L Mamrosh, Gang Lu, Brian E Cathers, Raymond J Deshaies
Glutamine synthetase (GS) plays an essential role in metabolism by catalyzing the synthesis of glutamine from glutamate and ammonia. Our recent study showed that CRBN, a direct protein target for the teratogenic and antitumor activities of immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide, recognizes an acetyl degron of GS, resulting in ubiquitylation and degradation of GS in response to glutamine. Here, we report that valosin-containing protein (VCP)/p97 promotes the degradation of ubiquitylated GS, resulting in its accumulation in cells with compromised p97 function...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28315680/selenoprotein-s-is-required-for-clearance-of-c99-through-endoplasmic-reticulum-associated-degradation
#6
Jun Ki Jang, Ki Jun Park, Jea Hwang Lee, Kwan Young Ko, Seongman Kang, Ick Young Kim
Amyloid beta precursor protein (APP) is normally cleaved by α-secretase, but can also be cleaved by β-secretase (BACE1) to produce C99 fragments in the endoplasmic reticulum (ER) membrane. C99 is subsequently cleaved to amyloid β (Aβ), the aggregation of which is known to cause Alzheimer's disease. Therefore, C99 removing is for preventing the disease. Selenoprotein S (SelS) is an ER membrane protein participating in endoplasmic reticulum-associated degradation (ERAD), one of the stages in resolving ER stress of misfolded proteins accumulated in the ER...
March 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28301499/svip-regulates-z-variant-alpha-1-antitrypsin-retro-translocation-by-inhibiting-ubiquitin-ligase-gp78
#7
Nazli Khodayari, Rejean Liqun Wang, George Marek, Karina Krotova, Mariana Kirst, Chen Liu, Farshid Rouhani, Mark Brantly
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT...
2017: PloS One
https://www.readbyqxmd.com/read/28131906/a-novel-hdac6-inhibitor-tubastatin-a-controls-hdac6-p97-vcp-mediated-ubiquitination-autophagy-turnover-and-reverses-temozolomide-induced-er-stress-tolerance-in-gbm-cells
#8
Zong-Yang Li, Ce Zhang, Yuan Zhang, Lei Chen, Bao-Dong Chen, Qing-Zhong Li, Xie-Jun Zhang, Wei-Ping Li
Temozolomide (TMZ) is the cornerstone of therapy for glioblastoma multiforme (GBM). However, its efficacy is limited due to the development of multidrug resistance (MDR). In this study, we first identified the occurrence of ER stress-tolerance (ERST) in glioma cells and confirmed that ERST was positively correlated with TMZ resistance. We further showed that the seesaw-effect of HDAC6-p97/VCP (increased HDAC6 and decreased p97/VCP) in glioma cells was crucial to ERST-associated TMZ resistance. Moreover, the combination treatment of Tubastatin A (TUB, a selective inhibitor of HDAC6) and TMZ synergistically overcame ERST, reduced cell viability and induced apoptosis in TMZ-resistant glioma cells...
January 26, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28096335/myofibril-breakdown-during-atrophy-is-a-delayed-response-requiring-the-transcription-factor-pax4-and-desmin-depolymerization
#9
Alexandra Volodin, Idit Kosti, Alfred Lewis Goldberg, Shenhav Cohen
A hallmark of muscle atrophy is the excessive degradation of myofibrillar proteins primarily by the ubiquitin proteasome system. In mice, during the rapid muscle atrophy induced by fasting, the desmin cytoskeleton and the attached Z-band-bound thin filaments are degraded after ubiquitination by the ubiquitin ligase tripartite motif-containing protein 32 (Trim32). To study the order of events leading to myofibril destruction, we investigated the slower atrophy induced by denervation (disuse). We show that myofibril breakdown is a two-phase process involving the initial disassembly of desmin filaments by Trim32, which leads to the later myofibril breakdown by enzymes, whose expression is increased by the paired box 4 (PAX4) transcription factor...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28049840/cytosolic-fc-receptor-trim21-inhibits-seeded-tau-aggregation
#10
William A McEwan, Benjamin Falcon, Marina Vaysburd, Dean Clift, Adrian L Oblak, Bernardino Ghetti, Michel Goedert, Leo C James
Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21)...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28036256/uv-induced-proteolysis-of-rna-polymerase-ii-is-mediated-by-vcp-p97-segregase-and-timely-orchestration-by-cockayne-syndrome-b-protein
#11
Jinshan He, Qianzheng Zhu, Gulzar Wani, Altaf A Wani
RNA polymerase II (RNAPII) acts as a damage sensor for transcription-coupled nucleotide excision repair (TC-NER) and undergoes proteolytic clearance from damaged chromatin by the ubiquitin-proteasome system (UPS). Here, we report that Valosin-containing protein (VCP)/p97, a druggable oncotarget, is essential for RNAPII's proteolytic clearance in mammalian cells. We show that inhibition of VCP/p97, or siRNA-mediated ablation of VCP/p97 and its cofactors UFD1 and UBXD7 severely impairs ultraviolet radiation (UVR)-induced RNAPII degradation...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28032027/valosin-containing-protein-is-a-target-of-5-l-fuligocandin%C3%A2-b-and-enhances-trail-resistance-in-cancer-cells
#12
Midori A Arai, Shota Taguchi, Kazuhiro Komatsuzaki, Kento Uchiyama, Ayaka Masuda, Mana Sampei, Mamoru Satoh, Sayaka Kado, Masami Ishibashi
Fuligocandin B (2) is a novel natural product that can overcome TRAIL resistance. We synthesized enatiomerically pure fuligocandin B (2) and its derivative 5'-I fuligocandin B (4), and found that the latter had an improved biological activity against the human gastric cancer cell line, AGS. We attached a biotin linker and photoactivatable aryl diazirine group to 5'-I fuligocandin B (4), and employed a pull-down assay to identify valosin-containing protein (VCP/p97), an AAA ATPase, as a 5'-I fuligocandin B (4) target protein...
December 2016: ChemistryOpen
https://www.readbyqxmd.com/read/27929047/caveolin-1-is-an-aggresome-inducing-protein
#13
Ajit Tiwari, Courtney A Copeland, Bing Han, Caroline A Hanson, Krishnan Raghunathan, Anne K Kenworthy
Caveolin-1 (Cav1) drives the formation of flask-shaped membrane invaginations known as caveolae that participate in signaling, clathrin-independent endocytosis and mechanotransduction. Overexpression or mutations of Cav1 can lead to its mistrafficking, including its accumulation in a perinuclear compartment previously identified as the Golgi complex. Here, we show that in the case of overexpressed Cav1-GFP, this perinuclear compartment consists of cytoplasmic inclusion bodies generated in response to the accumulation of aggregates of misfolded proteins, known as aggresomes...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27914931/valosin-containing-protein-vcp-p97-plays-a-role-in-the-replication-of-west-nile-virus
#14
Wallaya Phongphaew, Shintaro Kobayashi, Michihito Sasaki, Michael Carr, William W Hall, Yasuko Orba, Hirofumi Sawa
Valosin-containing protein (VCP) is classified as a member of the type II AAA(+) ATPase protein family. VCP functions in several cellular processes, including protein degradation, membrane fusion, vesicular trafficking and disassembly of stress granules. Moreover, VCP is considered to play a role in the replication of several viruses, albeit through different mechanisms. In the present study, we have investigated the role of VCP in West Nile virus (WNV) infection. Endogenous VCP expression was inhibited using either VCP inhibitors or by siRNA knockdown...
January 15, 2017: Virus Research
https://www.readbyqxmd.com/read/27887991/vcp-p97-regulates-%C3%AE-2ar-quality-control-during-receptor-biosynthesis
#15
Richard Wargachuk, Irina Glazkova, Nicolas Audet, Darlaine Pétrin, Phan Trieu, Terence E Hébert
GPCRs form signalling complexes with other receptors as part of dimers, G proteins and effector partners. A proteomic screen to identify proteins that associate with the β2-adrenergic receptor (β2AR) identified many of components of the Endoplasmic-Reticulum-Associated Degradation (ERAD) quality control system [1], including the valosin-containing protein (VCP/p97). Here, we validated the interaction of VCP with co-expressed FLAG-β2AR, demonstrating, using an inducible expression system, that the interaction of FLAG-β2AR and VCP is not an artifact of overexpression of the β2AR per se...
January 2017: Cellular Signalling
https://www.readbyqxmd.com/read/27861584/correction-ibmpfd-disease-causing-mutant-vcp-p97-proteins-are-targets-of-autophagic-lysosomal-degradation
#16
(no author information available yet)
[This corrects the article DOI: 10.1371/journal.pone.0164864.].
2016: PloS One
https://www.readbyqxmd.com/read/27828775/a-dynamic-molecular-basis-for-malfunction-in-disease-mutants-of-p97-vcp
#17
Anne K Schuetz, Lewis E Kay
p97/VCP is an essential, abundant AAA+ ATPase that is conserved throughout eukaryotes, with central functions in diverse processes ranging from protein degradation to DNA damage repair and membrane fusion. p97 has been implicated in the etiology of degenerative diseases and in cancer. Using Nuclear Magnetic Resonance spectroscopy we reveal how disease-causing mutations in p97 deregulate dynamics of the N-terminal domain that binds adaptor proteins involved in controlling p97 function. Our results provide a molecular basis for understanding how malfunction occurs whereby mutations shift the ADP-bound form of the enzyme towards an ATP-like state in a manner that correlates with disease severity...
November 9, 2016: ELife
https://www.readbyqxmd.com/read/27768726/ibmpfd-disease-causing-mutant-vcp-p97-proteins-are-targets-of-autophagic-lysosomal-degradation
#18
Oznur Bayraktar, Ozlem Oral, Nur Mehpare Kocaturk, Yunus Akkoc, Karin Eberhart, Ali Kosar, Devrim Gozuacik
The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone...
2016: PloS One
https://www.readbyqxmd.com/read/27753622/vcp-p97-cooperates-with-yod1-ubxd1-and-plaa-to-drive-clearance-of-ruptured-lysosomes-by-autophagy
#19
Chrisovalantis Papadopoulos, Philipp Kirchner, Monika Bug, Daniel Grum, Lisa Koerver, Nina Schulze, Robert Poehler, Alina Dressler, Sven Fengler, Khalid Arhzaouy, Vanda Lux, Michael Ehrmann, Conrad C Weihl, Hemmo Meyer
Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Together, they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation...
January 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/27735940/ddx3-dead-box-rna-helicase-plays-a-central-role-in-mitochondrial-protein-quality-control-in-leishmania
#20
Prasad Kottayil Padmanabhan, Ouafa Zghidi-Abouzid, Mukesh Samant, Carole Dumas, Bruno Guedes Aguiar, Jerome Estaquier, Barbara Papadopoulou
DDX3 is a highly conserved member of ATP-dependent DEAD-box RNA helicases with multiple functions in RNA metabolism and cellular signaling. Here, we describe a novel function for DDX3 in regulating the mitochondrial stress response in the parasitic protozoan Leishmania. We show that genetic inactivation of DDX3 leads to the accumulation of mitochondrial reactive oxygen species (ROS) associated with a defect in hydrogen peroxide detoxification. Upon stress, ROS production is greatly enhanced, causing mitochondrial membrane potential loss, mitochondrial fragmentation, and cell death...
October 13, 2016: Cell Death & Disease
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