DOCSLIB.ORG

MRI Opens Thrombolysis Window After Stroke

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
MRI Opens Thrombolysis Window After Stroke June 2005 • www.clinicalpsychiatrynews.com Neuropsychiatric Medicine 59 MRI Opens Thrombolysis Window After Stroke BY MITCHEL L. ZOLER rhage. Desmoteplase also has very high specifici- Philadelphia Bureau ty and selectivity for fibrin and a long serum half- life of 4 hours. This last property means that it can N EW O RLEANS — The presence of a favorable pat- be given as a bolus dose and may also help pre- tern of cerebral perfusion on magnetic resonance imag- vent acute reocclusion of newly opened arteries. ing may tell physicians which patients with acute ischemic Desmoteplase is being developed in the United stroke stand to benefit from thrombolysis even hours af- States by Forest Laboratories and in Europe by ter the onset of symptoms. PAION, a German drug company. Dr. Furlan is a Findings from two phase II studies using MRI show that consultant to both companies, and he received some patients were able to safely receive a thrombolytic compensation from both for acting as a principal drug as long as 9 hours after the onset of their stroke investigator in these and ongoing studies. symptoms. Results from the most recent of these stud- The U.S. study involved enrollment of 37 pa- ies were reported at the 30th International Stroke Con- tients who all met the entry MR criteria. After ference. randomization, 14 of the patients were treated Results from the prior study, which was conducted in with 90 mcg/kg desmoteplase, 15 received 125 NIVERSITY Europe, were published in January. mcg/kg desmoteplase, and 8 received placebo. U “These are the first trials to test the hypothesis that se- The average time to treatment was 7 hours. Al- ON lecting patients with favorable imaging patterns can ex- though patients could enter treatment as long as tend treatment beyond the current 3-hour window,” said 9 hours after the onset of their stroke symptoms, ASHINGT W T Anthony J. Furlan, M.D., head of the section of stroke and the top reason for excluding patients from the A neurologic intensive care at the Cleveland Clinic and prin- study was that they had gone beyond the 9-hour cipal investigator of the new study. window. ENTER “If this hypothesis is borne out, it could have an enor- The U.S. study’s primary end point was the rate C mous impact on how we use thrombolytic therapy for of symptomatic, intracranial hemorrhage (sICH), TROKE stroke,” he added. “It has the potential to at least triple which occurred in none of the patients. In the pri- S the number of acute stroke patients who are eligible for or European study, one sICH occurred among 15 NTERNET thrombolytic therapy.” patients treated with 90 mcg/kg and none among I Like the study done in Europe, Dr. Furlan’s research 15 patients treated with 125 mcg/kg. Thus, the In this T1-weighted MRI, a large infarct is clearly visible in used a combination of perfusion-weighted and diffusion- overall rate of sICH in these two studies at these the middle cerebral artery of an 18-year-old woman. weighted imaging by MR to identify patients with at two doses was one among 59 treated patients, a least a 20% mismatch between the two. 1.7% rate that was lower than the 6% rate with TPA in and 60% of those in the high-dose arm. There was no The mismatch is a marker for patients with a signifi- routine practice, noted Dr. Furlan at the conference, spon- reduction of safety or efficacy in the patients treated 6- cant penumbra region in their brain, tissue that might be sored by the American Stroke Association. 9 hours after their stroke onset, compared with those salvageable by thrombolytic therapy because it is still vi- In the European study, 30 patients received substantially treated 3-6 hours after onset, Dr. Furlan reported. able despite being hypoperfused. “Most patients who higher doses of desmoteplase, and they had a 27% rate The results were promising enough for a phase III study made it to MR were eligible,” Dr. Furlan said. “The MR of sICH. In this higher-dose group, the lowest to start this spring, retesting both desmoteplase doses criteria did not exclude a lot of patients.” desmoteplase dose associated with intracranial hemor- against placebo in a total of 186 patients, Dr. Furlan said. The other novel feature of both the European and U.S. rhage was 294 mcg/kg. The next study will also test perfusion CT imaging as well studies was the thrombolytic drug used: desmoteplase, a The new study was not powered to show significant dif- as MR imaging because some centers have easier access plasminogen activator derived from vampire bat saliva. ferences in clinical outcomes. to CT scanners. Desmoteplase has several potential advantages over tissue The reperfusion rate was 38% in the control group, If study results continue to document the safety and plasminogen activator (TPA). 18% among those who received 90 mcg/kg, and 53% efficacy of desmoteplase paired with imaging to identi- In animal studies, desmoteplase showed no neurotox- among those who received 125 mcg/kg. Improved clin- fy appropriate patients, eventually desmoteplase will icity, and it did not activate β-amyloid, a process that’s ical outcomes at 90 days were seen in 25% of those in have to be compared with TPA in a head-to-head study, been linked to an increased risk of intracranial hemor- the placebo group, 29% of those in the low-dose arm, he said. I Genetic Variant Increases Risk of Late-Onset Alzheimer’s BY SUSAN The mean age at disease onset was 72 Findings from the second investigation, sage. They found a relationship between LAWRENCE VOLKMAR years, the investigators said (N. Engl. J. the Consortium on Alzheimer’s Genetics the UBQ-8i allele and a UBQLN1 transcript Contributing Writer Med. 2005;352:884-94). study, showed that the rate of transmis- lacking exon 8 in the 25 samples from pa- Evaluation of 19 single-nucleotide poly- sion of the H3 haplotype was increased tients with Alzheimer’s disease. trategies for the prevention and treat- morphisms in three genes within the chro- among subjects with Alzheimer’s disease. In an accompanying editorial, Thomas Sment of late-onset Alzheimer’s disease mosome 9q linkage region showed that Investigators found no association with D. Bird, M.D., called UBQLN1 “intriguing may be improved by the identification of Alzheimer’s disease was significantly as- rs1411483 in APBA1. as a candidate gene because of its poten- a gene variant that seems to increase sociated with two single-nucleotide poly- Specimen collection began in 1999 and tial role in the proteasome degradation of Alzheimer’s disease, according to a report morphisms in UBQLN1 and one in APBA1. has been completed for 224 Alzheimer’s proteins and its interaction with PS1 and by Lars Bertram, M.D., of MassGeneral Haplotype block patients and 265 un- PS2.” Institute for Neurodegenerative Diseases, structure estimates Most genetic analyses of affected siblings. Af- “As always, this new association requires Charlestown, Mass., and his associates. showed that the sin- fected participants replication and confirmation in addition- Variants in the ubiquilin 1 (UBQLN1) gle haplotype (H3), Alzheimer’s were at least 50 years al populations,” commented Dr. Bird, gene, located on chromosome 9, may almost exclusively have been done on groups old at disease onset; who is professor of neurology, medicine, substantially increase the risk of late-on- defined by the risk mean age at onset and psychiatry at the University of Wash- set Alzheimer’s disease, which accounts allele of UBQ-8i, was too small to demonstrate was 71 years. ington, Seattle, and a research neurologist for over 90% of the disease, other inves- associated with a sig- moderate genetic effects Analyses by Dr. at the Veterans Affairs Medical Center in tigators have reported. nificantly increased Bertram and col- Seattle (N. Engl. J. Med. 2005;352:862-4). Dr. Bertram and his associates examined rate of transmission like that of UBQLN1. leagues on data Dr. Bertram’s group observed that “the two groups of patients; the first consisted to affected subjects. merged from the two rampant inconsistencies encountered in of 1,439 subjects from 437 families with The testing of APBA1 polymorphisms did family groups showed the most pro- genetic analyses of putative candidate Alzheimer’s disease who participated in not indicate such transmission. nounced single-local signals for UBQ-8i genes for Alzheimer’s disease in the liter- the National Institute of Mental Health Ubiquilin 1 encodes the protein followed by rs2781002 and rs2780995. ature to date” may stem from the fact that multiplex family study between 1991 and ubiquilin 1, regulates protein degradation, Dr. Bertram’s group also studied RNA most studies are done on groups too 1997. Of that group, 994 patients had interacts with presenilin 1 and presenilin extracts from neocortical brain tissue sam- small to show moderate genetic effects Alzheimer’s, 411 were unaffected, and 34 2, and promotes the accumulation of pre- ples to see if the risk allele UBQ-8i affects like that of UBQLN1, instead of the more had unknown phenotypes. senilin in vitro, they said. the splicing of exon 8 in the UBQLN1 mes- pronounced effects of APOE. I.
Load more

Recommended publications
  • Pathognomonic and Epistatic Genetic Alterations in B-Cell Non-Hodgkin
    bioRxiv preprint doi: https://doi.org/10.1101/674259; this version posted June 19, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Pathognomonic and epistatic genetic alterations in 2 B-cell non-Hodgkin lymphoma 3 4 Man Chun John Ma1¥, Saber Tadros1¥, Alyssa Bouska2, Tayla B. Heavican2, Haopeng Yang1, 5 Qing Deng1, Dalia Moore3, Ariz Akhter4, Keenan Hartert3, Neeraj Jain1, Jordan Showell1, 6 Sreejoyee Ghosh1, Lesley Street5, Marta Davidson5, Christopher Carey6, Joshua Tobin7, 7 Deepak Perumal8, Julie M. Vose9, Matthew A. Lunning9, Aliyah R. Sohani10, Benjamin J. 8 Chen11, Shannon Buckley12, Loretta J. Nastoupil1, R. Eric Davis1, Jason R. Westin1, Nathan H. 9 Fowler1, Samir Parekh8, Maher K. Gandhi7, Sattva S. Neelapu1, Douglas Stewart5, Javeed 10 Iqbal2, Timothy Greiner2, Scott J. Rodig13, Adnan Mansoor5, Michael R. Green1,14,15* 11 1Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD 12 Anderson Cancer Center, Houston, TX, USA; 2Department of Pathology and Microbiology, University of 13 Nebraska Medical Center, Omaha, NE, USA; 3Eppley Institute for Research in Cancer and Allied 14 Diseases, University of Nebraska Medical Center, Omaha, NE, USA; 4Department of Pathology and 15 Laboratory Medicine, University of Calgary, Calgary, AB, Canada; 5Section of Hematology, Department of 16 Medicine, University
    [Show full text]
  • Nuclear Export of Ubiquitinated Proteins Via the UBIN-POST System
    Nuclear export of ubiquitinated proteins via the PNAS PLUS UBIN-POST system Shoshiro Hirayamaa,1,2, Munechika Sugiharab,1, Daisuke Moritoc,d, Shun-ichiro Iemurae, Tohru Natsumee, Shigeo Murataa, and Kazuhiro Nagatab,c,d,2 aLaboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033, Japan; bFaculty of Life Sciences, Kyoto Sangyo University, Kyoto, 603-8555, Japan; cInstitute for Protein Dynamics, Kyoto Sangyo University, Kyoto, 603-8555, Japan; dCore Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama, 332-0012, Japan; and eBiomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, 135-0064, Japan Edited by Brenda A. Schulman, Max Planck Institute of Biochemistry, Martinsried, Germany, and approved March 19, 2018 (received for review June 19, 2017) Although mechanisms for protein homeostasis in the cytosol have folding enzymes with a broad range of activities, two strong and been studied extensively, those in the nucleus remain largely flexible proteolytic machineries (namely, the UPS and autophagy), unknown. Here, we identified that a protein complex mediates and regulated protein deposition systems, such as the aggresome, export of polyubiquitinated proteins from the nucleus to the aggresome-like induced structure (ALIS), insoluble protein de- cytosol. UBIN, a ubiquitin-associated (UBA) domain-containing pro- posit (IPOD), and juxta nuclear quality control compartment tein, shuttled between the nucleus and the cytosol in a CRM1- (JUNQ), which sequester damaged proteins (9–11). Thus, the dependent manner, despite the lack of intrinsic nuclear export signal cytosol constitutes a robust system for maintaining protein ho- (NES). Instead, the UBIN binding protein polyubiquitinated substrate meostasis that extends to distinct organelles within the cytosol.
    [Show full text]
  • RTL8 Promotes Nuclear Localization of UBQLN2 to Subnuclear Compartments Associated with Protein Quality Control
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.21.440788; this version posted April 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Title: RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control Harihar Milaganur Mohan1,2, Amit Pithadia1, Hanna Trzeciakiewicz1, Emily V. Crowley1, Regina Pacitto1 Nathaniel Safren1,3, Chengxin Zhang4, Xiaogen Zhou4, Yang Zhang4, Venkatesha Basrur5, Henry L. Paulson1,*, Lisa M. Sharkey1,* 1. Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200 2. Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109- 2200 3. Present address: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 4. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2200 5. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109. *Corresponding authors: Henry Paulson: Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200; [email protected]; Tel. (734) 615-5632; Fax. (734) 615-5655 Lisa M Sharkey: Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200; [email protected]; Tel. (734) 763-3496; Fax (734) 615-5655 Keywords: Ubiquilin, UBQLN2, RTL8, Nuclear Protein Quality Control, Ubiquitin Proteasome System Declarations Funding: This work was supported by NIH 9R01NS096785-06, 1P30AG053760-01, The Amyotrophic Lateral Sclerosis Foundation and the UM Protein Folding Disease Initiative. Conflicts of interest/Competing interests: None declared Availability of data and material: • The authors confirm that the data supporting the findings in this are available within the article, at repository links provided within the article, and within its supplementary files.
    [Show full text]
  • E-Mutpath: Computational Modelling Reveals the Functional Landscape of Genetic Mutations Rewiring Interactome Networks
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.262386; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. e-MutPath: Computational modelling reveals the functional landscape of genetic mutations rewiring interactome networks Yongsheng Li1, Daniel J. McGrail1, Brandon Burgman2,3, S. Stephen Yi2,3,4,5 and Nidhi Sahni1,6,7,8,* 1Department oF Systems Biology, The University oF Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2Department oF Oncology, Livestrong Cancer Institutes, Dell Medical School, The University oF Texas at Austin, Austin, TX 78712, USA 3Institute For Cellular and Molecular Biology (ICMB), The University oF Texas at Austin, Austin, TX 78712, USA 4Institute For Computational Engineering and Sciences (ICES), The University oF Texas at Austin, Austin, TX 78712, USA 5Department oF Biomedical Engineering, Cockrell School of Engineering, The University oF Texas at Austin, Austin, TX 78712, USA 6Department oF Epigenetics and Molecular Carcinogenesis, The University oF Texas MD Anderson Science Park, Smithville, TX 78957, USA 7Department oF BioinFormatics and Computational Biology, The University oF Texas MD Anderson Cancer Center, Houston, TX 77030, USA 8Program in Quantitative and Computational Biosciences (QCB), Baylor College oF Medicine, Houston, TX 77030, USA *To whom correspondence should be addressed. Nidhi Sahni. Tel: +1 512 2379506; Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.262386; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • RTL8 Promotes Nuclear Localization of UBQLN2 to Subnuclear Compartments Associated with Protein Quality Control
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.21.440788; this version posted April 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Title: RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control Harihar Milaganur Mohan1,2, Amit Pithadia1, Hanna Trzeciakiewicz1, Emily V. Crowley1, Regina Pacitto1 Nathaniel Safren1,3, Chengxin Zhang4, Xiaogen Zhou4, Yang Zhang4, Venkatesha Basrur5, Henry L. Paulson1,*, Lisa M. Sharkey1,* 1. Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200 2. Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109- 2200 3. Present address: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 4. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2200 5. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109. *Corresponding authors: Henry Paulson: Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200; [email protected]; Tel. (734) 615-5632; Fax. (734) 615-5655 Lisa M Sharkey: Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200; [email protected]; Tel. (734) 763-3496; Fax (734) 615-5655 Keywords: Ubiquilin, UBQLN2, RTL8, Nuclear Protein Quality Control, Ubiquitin Proteasome System Declarations Funding: This work was supported by NIH 9R01NS096785-06, 1P30AG053760-01, The Amyotrophic Lateral Sclerosis Foundation and the UM Protein Folding Disease Initiative. Conflicts of interest/Competing interests: None declared Availability of data and material: • The authors confirm that the data supporting the findings in this are available within the article, at repository links provided within the article, and within its supplementary files.
    [Show full text]
  • Roles of Xbp1s in Transcriptional Regulation of Target Genes
    biomedicines Review Roles of XBP1s in Transcriptional Regulation of Target Genes Sung-Min Park , Tae-Il Kang and Jae-Seon So * Department of Medical Biotechnology, Dongguk University, Gyeongju 38066, Gyeongbuk, Korea; [email protected] (S.-M.P.); [email protected] (T.-I.K.) * Correspondence: [email protected] Abstract: The spliced form of X-box binding protein 1 (XBP1s) is an active transcription factor that plays a vital role in the unfolded protein response (UPR). Under endoplasmic reticulum (ER) stress, unspliced Xbp1 mRNA is cleaved by the activated stress sensor IRE1α and converted to the mature form encoding spliced XBP1 (XBP1s). Translated XBP1s migrates to the nucleus and regulates the transcriptional programs of UPR target genes encoding ER molecular chaperones, folding enzymes, and ER-associated protein degradation (ERAD) components to decrease ER stress. Moreover, studies have shown that XBP1s regulates the transcription of diverse genes that are involved in lipid and glucose metabolism and immune responses. Therefore, XBP1s has been considered an important therapeutic target in studying various diseases, including cancer, diabetes, and autoimmune and inflammatory diseases. XBP1s is involved in several unique mechanisms to regulate the transcription of different target genes by interacting with other proteins to modulate their activity. Although recent studies discovered numerous target genes of XBP1s via genome-wide analyses, how XBP1s regulates their transcription remains unclear. This review discusses the roles of XBP1s in target genes transcriptional regulation. More in-depth knowledge of XBP1s target genes and transcriptional regulatory mechanisms in the future will help develop new therapeutic targets for each disease. Citation: Park, S.-M.; Kang, T.-I.; Keywords: XBP1s; IRE1; ATF6; ER stress; unfolded protein response; UPR; RIDD So, J.-S.
    [Show full text]
  • Shared and Divergent Phase Separation and Aggregation Properties of Brain‑Expressed Ubiquilins Julia E
    www.nature.com/scientificreports OPEN Shared and divergent phase separation and aggregation properties of brain‑expressed ubiquilins Julia E. Gerson1*, Hunter Linton1, Jiazheng Xing1, Alexandra B. Sutter1,3, Fayth S. Kakos1, Jaimie Ryou1, Nyjerus Liggans1, Lisa M. Sharkey1, Nathaniel Safren1,4, Henry L. Paulson1* & Magdalena I. Ivanova1,2* The brain‑expressed ubiquilins, UBQLNs 1, 2 and 4, are highly homologous proteins that participate in multiple aspects of protein homeostasis and are implicated in neurodegenerative diseases. Studies have established that UBQLN2 forms liquid‑like condensates and accumulates in pathogenic aggregates, much like other proteins linked to neurodegenerative diseases. However, the relative condensate and aggregate formation of the three brain‑expressed ubiquilins is unknown. Here we report that the three ubiquilins difer in aggregation propensity, revealed by in-vitro experiments, cellular models, and analysis of human brain tissue. UBQLN4 displays heightened aggregation propensity over the other ubiquilins and, like amyloids, UBQLN4 forms ThiofavinT‑positive fbrils in vitro. Measuring fuorescence recovery after photobleaching (FRAP) of puncta in cells, we report that all three ubiquilins undergo liquid–liquid phase transition. UBQLN2 and 4 exhibit slower recovery than UBQLN1, suggesting the condensates formed by these brain‑expressed ubiquilins have diferent compositions and undergo distinct internal rearrangements. We conclude that while all brain‑ expressed ubiquilins exhibit self‑association behavior manifesting as condensates, they follow distinct courses of phase‑separation and aggregation. We suggest that this variability among ubiquilins along the continuum from liquid‑like to solid informs both the normal ubiquitin‑linked functions of ubiquilins and their accumulation and potential contribution to toxicity in neurodegenerative diseases.
    [Show full text]
  • Ubiquilin Proteins Regulate EGFR Levels and Activity in Lung
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.03.131888; this version posted June 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Ubiquilin proteins regulate EGFR levels and activity in lung 2 adenocarcinoma cells 3 Running title: Regulation of EGFR by UBQLN proteins 4 Authors: Zimple Kurlawala1*5, Kumar Saurabh1*, Rain Dunaway2, Parag P. Shah1, Leah 5 J. Siskind1,3 and Levi J. Beverly1,3,4,# 6 Affiliations: 7 1James Graham Brown Cancer Center, School of Medicine, University of Louisville, 8 Louisville, KY USA. 9 2School of Medicine, University of Louisville, KY, USA 10 3Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 11 USA. 12 4Division of Hematology and Oncology, School of Medicine, University of Louisville, 13 Louisville, KY, USA. 14 5Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of 15 Health, Baltimore, MD, USA (author’s present address). 16 *Equal authors 17 #Corresponding author (Email: [email protected]) 18 19 Abstract 20 Ubiquilin proteins (UBQLNs) are involved in diverse cellular processes like ERAD 21 (endoplasmic reticulum associated degradation), autophagy, apoptosis and epithelial to 22 mesenchymal transition. UBQLNs interact with a variety of substrates, including cell 23 surface receptors, transcription factor regulators, proteasomal machinery proteins, and 24 transmembrane proteins. Additionally, previous work from our lab shows that UBQLN1 25 interacts with IGFR family members (IGF1R, IGF2R, INSR) and this interaction regulates 26 the activity and proteostasis of IGFR family members.
    [Show full text]
  • The Impacts of Ubiquilin 1 (UBQLN1) Knockdown on Cells Viability, Proliferation, and Apoptosis Are Mediated by P53 in A549 Lung Cancer Cells
    5895 Original Article The impacts of ubiquilin 1 (UBQLN1) knockdown on cells viability, proliferation, and apoptosis are mediated by p53 in A549 lung cancer cells Xinghua Zhang1, Yunshu Su1, Huiqing Lin1, Xiaoli Yao2 1Department of Thoracic Surgery, 2Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China Contributions: (I) Conception and design: X Zhang, X Yao; (II) Administrative support: H Lin, X Yao; (III) Provision of study materials or patients: X Zhang, Y Su; (IV) Collection and assembly of data: X Zhang, Y Su; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Xiaoli Yao. Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, 238# Jiefang Road, Wuhan 430060, China. Email: [email protected]. Background: Little is known about the relationship between ubiquilin 1 (UBQLN1) and p53, both of them have been implicated in the development and progression of non-small cell lung cancer (NSCLC). In this study, we aimed to explore the role of loss of UBQLN1 in cell viability and proliferation, and cell apoptosis in human lung adenocarcinoma A549 cells. Methods: Cell viability, proliferation, and apoptosis were determined by MTT, BrdU, and TUNEL assays, respectively. Adenoviruses carrying cDNA or siRNA were used to overexpress or silence target protein. Dihydroethidium (DHE) staining was performed to measure the real-time formation of intracellular reactive oxygen species (ROS). The chymotrypsin-like activity of 20S proteasome core was determined by using synthetic fluorogenic peptide substrate. Results: UBQLN1 silencing led to a reduction of p53 protein levels and overexpression of p53 reversed the effects of UBQLN1 knockdown (KD) on cell viability, proliferation, and apoptosis.
    [Show full text]
  • Trafficking Regulation of Proteins in Alzheimer's Disease
    Jiang et al. Molecular Neurodegeneration 2014, 9:6 http://www.molecularneurodegeneration.com/content/9/1/6 REVIEW Open Access Trafficking regulation of proteins in Alzheimer’s disease Shangtong Jiang1,2†, Yanfang Li2†, Xian Zhang2, Guojun Bu2,3, Huaxi Xu1,2,4 and Yun-wu Zhang2* Abstract The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD. Keywords: α-secretase, Amyloid beta (A4) precursor protein, β-secretase, Beta-site APP-cleaving enzyme 1, γ-secretase, A Disintegrin and Metalloprotease 10, Alzheimer’s disease, Trafficking Introduction APP β-carboxyl-terminal fragment (β-CTF) is then Alzheimer’s disease (AD) is a progressive neurodegenera- cleaved by the γ-secretase complex within the lipid bilayer, tive disorder characterized clinically by cognitive and resulting in the production of Aβ peptide and the APP memory dysfunction, accompanied by classical hallmark intracellular domain (AICD). Alternatively, processing pathologies such as intraneuronal neurofibrillary tangles within the non-amyloidogenic pathway involves APP (NFTs) and extracellular amyloid plaques [1-3]. NFTs cleavage by α-secretase within the Aβ domain. The α- are enriched with hyperphosphorylated microtubule-asso- cleavage releases the extracellular domain of APP called ciated protein tau (MAPT) [2], which can be phospho- sAPPα.
    [Show full text]
  • Structure of Hrpn10 Bound to UBQLN2 UBL Illustrates Basis for Complementarity Between Shuttle Factors and Substrates at the Proteasome
    Article Structure of hRpn10 Bound to UBQLN2 UBL Illustrates Basis for Complementarity between Shuttle Factors and Substrates at the Proteasome Xiang Chen 1, Danielle L. Ebelle 1, Brandon J. Wright 1, Vinidhra Sridharan 1, Evan Hooper 1,2 and Kylie J. Walters 1 1 - Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA 2 - Linganore High School, Frederick, MD 21701, USA Correspondence to Kylie J. Walters: [email protected] https://doi.org/10.1016/j.jmb.2019.01.021 Edited by Titia Sixma Abstract The 26S proteasome is a highly complex 2.5-MDa molecular machine responsible for regulated protein degradation. Proteasome substrates are typically marked by ubiquitination for recognition at receptor sites contributed by Rpn1/S2/PSMD2, Rpn10/S5a, and Rpn13/Adrm1. Each receptor site can bind substrates directly by engaging conjugated ubiquitin chains or indirectly by binding to shuttle factors Rad23/HR23, Dsk2/ PLIC/UBQLN, or Ddi1, which contain a ubiquitin-like domain (UBL) that adopts the ubiquitin fold. Previous structural studies have defined how each of the proteasome receptor sites binds to ubiquitin chains as well as some of the interactions that occur with the shuttle factors. Here, we define how hRpn10 binds to the UBQLN2 UBL domain, solving the structure of this complex by NMR, and determine affinities for each UIM region by a titration experiment. UBQLN2 UBL exhibits 25-fold stronger affinity for the N-terminal UIM-1 over UIM-2 of hRpn10. Moreover, we discover that UBQLN2 UBL is fine-tuned for the hRpn10 UIM-1 site over the UIM-2 site by taking advantage of the additional contacts made available through the longer UIM-1 helix.
    [Show full text]
  • UBQLN1 Mediates Sorafenib Resistance Through Regulating Mitochondrial Biogenesis and ROS Homeostasis by Targeting Pgc1β in Hepatocellular Carcinoma
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans ARTICLE OPEN UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1β in hepatocellular carcinoma Junjie Xu1,2,3,4, Lin Ji1,2, Yeling Ruan1,2, Zhe Wan1,2, Zhongjie Lin1,2, Shunjie Xia1,2, Liye Tao1,2, Junhao Zheng1,2, Liuxin Cai1,2, Yifan Wang1,2,3,4, Xiao Liang1,2,3,4 and Xiujun Cai 1,2,3,4 The treatment for hepatocellular carcinoma (HCC) is promising in recent years, but still facing critical challenges. The first targeted therapy, sorafenib, prolonged the overall survival by months. However, resistance often occurs, largely limits its efficacy. Sorafenib was found to target the electron transport chain complexes, which results in the generation of reactive oxygen species (ROS). To maintain sorafenib resistance and further facilitate tumor progression, cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death. In the present study, we investigated the roles of ROS in sorafenib resistance, and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells. Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib. However, cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib- resistant cells. Further investigation attributed this finding to decreased mitochondrial biogenesis, likely caused by the accelerated degradation of peroxisome proliferator-activated receptor γ coactivator 1β (PGC1β). Mechanistic dissection showed that 1234567890();,: upregulated UBQLN1 induced PGC1β degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment.
    [Show full text]