LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 10 of total 13

Search options

  1. Article: [Rezension von: DeMartino, George F., Global economy, global justice]

    Toruño, Mayo C / DeMartino, George

    Journal of economic issues : jei Vol. 35, No. 1 , p. 214-216

    2001  Volume 35, Issue 1, Page(s) 214–216

    Author's details Mayo C. Toruño
    Keywords 40#49
    Language English
    Publisher Taylor & Francis Group
    Publishing place Philadelphia, Pa
    Document type Article
    ZDB-ID 410536-9 ; 2066505-2
    ISSN 1946-326X ; 0021-3624
    ISSN (online) 1946-326X
    ISSN 0021-3624
    Database ECONomics Information System

    More links

    Kategorien

  2. Article ; Online: The specter of irreparable ignorance: counterfactuals and causality in economics.

    DeMartino, George F

    Review of evolutionary political economy

    2021  Volume 2, Issue 2, Page(s) 253–276

    Abstract: Those economists who have emphasized true uncertainty have tended to draw an epistemic distinction between an ascertainable past and an unknowable future. But in one critical respect-in extracting causal relationships-that epistemic distinction is not ... ...

    Abstract Those economists who have emphasized true uncertainty have tended to draw an epistemic distinction between an ascertainable past and an unknowable future. But in one critical respect-in extracting causal relationships-that epistemic distinction is not warranted. Whether they are situated in the past or future, causal arguments in economics depend equally on counterfactual reasoning. Counterfactualizing entails the construction of fictitious narratives-narratives about worlds that do not exist. Unfortunately, there is no dependable method for ascertaining the uniquely correct counterfactual. This implies that causal claims in economics, too, are irreducibly fictitious. The chief value of counterfactuals, then, is not to prove causation but to help scholars and practitioners confront an inscrutable world-to imagine and prepare for unknowable possible futures. In this endeavor, economic pluralism, which expands the range of plausible counterfactuals, is to be taken as a virtue rather than a curse.
    Language English
    Publishing date 2021-01-08
    Publishing country Switzerland
    Document type Journal Article
    ISSN 2662-6144
    ISSN (online) 2662-6144
    DOI 10.1007/s43253-020-00029-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  3. Article ; Online: Highly conserved shifts in ubiquitin-proteasome system (UPS) activity drive mitochondrial remodeling during quiescence.

    Yue, Sibiao / Wang, Lei / DeMartino, George N / Zhao, FangZhou / Liu, Yi / Sieber, Matthew H

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 4462

    Abstract: Defects in cellular proteostasis and mitochondrial function drive many aspects of infertility, cancer, and other age-related diseases. All of these conditions rely on quiescent cells, such as oocytes and adult stem cells, that reduce their activity and ... ...

    Abstract Defects in cellular proteostasis and mitochondrial function drive many aspects of infertility, cancer, and other age-related diseases. All of these conditions rely on quiescent cells, such as oocytes and adult stem cells, that reduce their activity and remain dormant as part of their roles in tissue homeostasis, reproduction, and even cancer recurrence. Using a multi-organism approach, we show that dynamic shifts in the ubiquitin proteasome system drive mitochondrial remodeling during cellular quiescence. In contrast to the commonly held view that the ubiquitin-proteasome system (UPS) is primarily regulated by substrate ubiquitination, we find that increasing proteasome number and their recruitment to mitochondria support mitochondrial respiratory quiescence (MRQ). GSK3 triggers proteasome recruitment to the mitochondria by phosphorylating outer membrane proteins, such as VDAC, and suppressing mitochondrial fatty acid oxidation. This work defines a process that couples dynamic regulation of UPS activity to coordinated shifts in mitochondrial metabolism in fungi, Drosophila, and mammals during quiescence.
    MeSH term(s) Animals ; Glycogen Synthase Kinase 3/metabolism ; Mammals/metabolism ; Mitochondria/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Ubiquitination
    Chemical Substances Ubiquitin ; Glycogen Synthase Kinase 3 (EC 2.7.11.26) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2022-08-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-32206-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  4. Article: [Rezension von: DeMartino, George, Global economy, global justice]

    Toye, John F. J / DeMartino, George

    The economic journal : the journal of the Royal Economic Society Vol. 111 , p. F504-505

    2001  Volume 111

    Author's details rezensiert von:] John Toye
    Keywords 40#49
    Language English
    Publisher Wiley-Blackwell
    Publishing place Oxford [u.a.]
    Document type Article
    ZDB-ID 3025-9 ; 1473822-3
    ISSN 1468-0297 ; 0013-0133
    ISSN (online) 1468-0297
    ISSN 0013-0133
    Database ECONomics Information System

    More links

    Kategorien

  5. Article ; Online: Modification of Cul1 regulates its association with proteasomal subunits.

    Bloom, Joanna / Peschiaroli, Angelo / Demartino, George / Pagano, Michele

    Cell division

    2006  Volume 1, Page(s) 5

    Abstract: ... plant ubiquitin ligases, including the highly conserved SCF (Skp1/Cul1/F-box protein) complex, have been ...

    Abstract Background: Ubiquitylation targets proteins for degradation by the 26S proteasome. Some yeast and plant ubiquitin ligases, including the highly conserved SCF (Skp1/Cul1/F-box protein) complex, have been shown to associate with proteasomes. We sought to characterize interactions between SCF complexes and proteasomes in mammalian cells.
    Results: We found that the binding of SCF complexes to proteasomes is conserved in higher eukaryotes. The Cul1 subunit associated with both sub-complexes of the proteasome, and high molecular weight forms of Cul1 bound to the 19S proteasome. Cul1 is ubiquitylated in vivo. Ubiquitylation of Cul1 promotes its binding to the S5a subunit of the 19S sub-complex without affecting Cul1 stability.
    Conclusion: The association of ubiquitylating enzymes with proteasomes may be an additional means to target ubiquitylated substrates for degradation.
    Language English
    Publishing date 2006-04-28
    Publishing country England
    Document type Journal Article
    ISSN 1747-1028
    ISSN (online) 1747-1028
    DOI 10.1186/1747-1028-1-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  6. Article ; Online: In situ bypass and extra-anatomic bypass procedures result in similar survival in patients with secondary aortoenteric fistulas.

    Janko, Matthew R / Woo, Karen / Hacker, Robert I / Baril, Donald / Bath, Jonathan / Smeds, Matthew R / Kashyap, Vikram S / Szeberin, Zoltan / Magee, Gregory A / Elsayed, Ramsey / Wishy, Andrew / St John, Rebecca / Beck, Adam / Farber, Mark / Motta, Fernando / Zhou, Wei / Lemmon, Gary / Coleman, Dawn / Behrendt, Christian-Alexander /
    Aziz, Faisal / Black, James / Shutze, William / Garrett, H Edward / De Caridi, Giovanni / Liapis, Christos D / Geroulakos, George / Kakisis, John / Moulakakis, Konstantinos / Kakkos, Stavros K / Obara, Hideaki / Wang, Grace / Rhéaume, Pascal / Davila, Victor / Ravin, Reid / DeMartino, Randall / Milner, Ross / Shalhub, Sherene / Jim, Jeffrey / Lee, Jason / Dubuis, Celine / Ricco, Jean-Baptiste / Coselli, Joseph / Lemaire, Scott / Fatima, Javairiah / Sanford, Jennifer / Yoshida, Winston / Schermerhorn, Marc L / Menard, Matthew / Belkin, Michael / Blackwood, Stuart / Conrad, Mark / Wang, Linda / Crofts, Sara / Nixon, Thomas / Wu, Timothy / Chiesa, Roberto / Bose, Saideep / Turner, Jason / Moore, Ryan / Smith, Justin / Ciocca, Rocco / Hsu, Jeffrey / Czerny, Martin / Cullen, Jonathan / Kahlberg, Andrea / Setacci, Carlo / Joh, Jin Hyun / Senneville, Eric / Garrido, Pedro / Sarac, Timur P / Rizzo, Anthony / Go, Michael R / Bjorck, Martin / Gavali, Hamid / Wanhainen, Anders / Lawrence, Peter F / Chung, Jayer

    Journal of vascular surgery

    2020  Volume 73, Issue 1, Page(s) 210–221.e1

    Abstract: Objective: The optimal revascularization modality in secondary aortoenteric fistula (SAEF) remains unclear in the literature. The purpose of this investigation was to determine the revascularization approach associated with the lowest morbidity and ... ...

    Abstract Objective: The optimal revascularization modality in secondary aortoenteric fistula (SAEF) remains unclear in the literature. The purpose of this investigation was to determine the revascularization approach associated with the lowest morbidity and mortality using real-world data in patients with SAEF.
    Methods: A retrospective, multi-institutional study of SAEF from 2002 to 2014 was performed using a standardized database. Baseline demographics, comorbidities, and operative and postoperative variables were recorded. The primary outcome was long-term mortality. Descriptive statistics, Kaplan-Meier survival analysis, and univariate and multivariate analyses were performed.
    Results: During the study period, 182 patients at 34 institutions from 11 countries presented with SAEF (median age, 72 years; 79% male). The initial aortic procedures that resulted in SAEF were 138 surgical grafts (76%) and 42 endografts (23%), with 2 unknown; 102 of the SAEFs (56%) underwent complete excision of infected aortic graft material, followed by in situ (in-line) bypass (ISB), including antibiotic-soaked prosthetic graft (53), autogenous femoral vein (neoaortoiliac surgery; 17), cryopreserved allograft (28), and untreated prosthetic grafts (4). There were 80 patients (44%) who underwent extra-anatomic bypass (EAB) with infected graft excision. Overall median Kaplan-Meier estimated survival was 319 days (interquartile range, 20-2410 days). Stratified by EAB vs ISB, there was no significant difference in Kaplan-Meier estimated survival (P = .82). In comparing EAB vs ISB, EAB patients were older (74 vs 70 years; P = .01), had less operative hemorrhage (1200 mL vs 2000 mL; P = .04), were more likely to initiate dialysis within 30 days postoperatively (15% vs 5%; P = .02), and were less likely to experience aorta-related hemorrhage within 30 days postoperatively (3% aortic stump dehiscence vs 11% anastomotic rupture; P = .03). There were otherwise no significant differences in presentation, comorbidities, and intraoperative or postoperative variables. Multivariable Cox regression showed that the duration of antibiotic use (hazard ratio, 0.92; 95% confidence interval, 0.86-0.98; P = .01) and rifampin use at time of discharge (hazard ratio, 0.20; 95% confidence interval, 0.05-0.86; P = .03) independently decreased mortality.
    Conclusions: These data suggest that ISB does not offer a survival advantage compared with EAB and does not decrease the risk of postoperative aorta-related hemorrhage. After repair, <50% of SAEF patients survive 10 months. Each week of antibiotic use decreases mortality by 8%. Further study with risk modeling is imperative for this population.
    MeSH term(s) Aged ; Blood Vessel Prosthesis Implantation/methods ; Female ; Follow-Up Studies ; Humans ; Intestinal Fistula/diagnosis ; Intestinal Fistula/mortality ; Intestinal Fistula/surgery ; Male ; Middle Aged ; Retrospective Studies ; Stents ; Survival Rate/trends ; United States/epidemiology ; Vascular Fistula/diagnosis ; Vascular Fistula/mortality ; Vascular Fistula/surgery
    Language English
    Publishing date 2020-05-21
    Publishing country United States
    Document type Journal Article ; Multicenter Study
    ZDB-ID 605700-7
    ISSN 1097-6809 ; 0741-5214
    ISSN (online) 1097-6809
    ISSN 0741-5214
    DOI 10.1016/j.jvs.2020.04.515
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  7. Article ; Online: Contemporary Outcomes After Partial Resection of Infected Aortic Grafts.

    Janko, Matthew / Hubbard, Grant / Woo, Karen / Kashyap, Vikram S / Mitchell, Megan / Murugesan, Arun / Chen, Lin / Gardner, Rachel / Baril, Donald / Hacker, Robert I / Szeberin, Zoltan / ElSayed, Ramsey / Magee, Gregory A / Motta, Fernando / Zhou, Wei / Lemmon, Gary / Coleman, Dawn / Behrendt, Christian-Alexander / Aziz, Faisal /
    Black, James H / Tran, Kimberly / Dao, Allen / Shutze, William / Garrett, H Edward / De Caridi, Giovanni / Patel, Rhusheet / Liapis, Christos D / Geroulakos, George / Kakisis, John / Moulakakis, Konstantinos / Kakkos, Starvos K / Obara, Hideaki / Wang, Grace / Stoecker, Jordan / Rhéaume, Pascal / Davila, Victor / Ravin, Reid / DeMartino, Randall / Milner, Ross / Shalhub, Sherene / Jim, Jeffrey / Lee, Jason / Dubuis, Celine / Ricco, Jean-Baptiste / Coselli, Joseph / Lemaire, Scott / Fatima, Javairiah / Sanford, Jennifer / Yoshida, Winston / Schermerhorn, Marc L / Menard, Matthew / Belkin, Michael / Blackwood, Stuart / Conrad, Mark / Wang, Linda / Crofts, Sara / Nixon, Thomas / Wu, Timothy / Chiesa, Roberto / Bose, Saideep / Turner, Jason / Moore, Ryan / Smith, Justin / Irshad, Ali / Hsu, Jeffrey / Czerny, Martin / Cullen, Jonathan / Kahlberg, Andrea / Setacci, Carlo / Joh, Jin Hyun / Senneville, Eric / Garrido, Pedro / Sarac, Timur P / Rizzo, Anthony / Go, Michael R / Bjorck, Martin / Gavali, Hamid / Wanhainen, Anders / D'Oria, Mario / Lepidi, Sandro / Mastrorilli, Davide / Veraldi, Gianfranco / Piazza, Michele / Squizzato, Francesco / Beck, Adam / St John, Rebecca / Wishy, Andrew / Humphries, Misty / Shah, Samir K / Back, Martin / Chung, Jayer / Lawrence, Peter F / Bath, Jonathan / Smeds, Matthew R

    Annals of vascular surgery

    2021  Volume 76, Page(s) 202–210

    Abstract: Introduction: Aortic graft infection remains a considerable clinical challenge, and it is unclear which variables are associated with adverse outcomes among patients undergoing partial resection.: Methods: A retrospective, multi-institutional study ... ...

    Abstract Introduction: Aortic graft infection remains a considerable clinical challenge, and it is unclear which variables are associated with adverse outcomes among patients undergoing partial resection.
    Methods: A retrospective, multi-institutional study of patients who underwent partial resection of infected aortic grafts from 2002 to 2014 was performed using a standard database. Baseline demographics, comorbidities, operative, and postoperative variables were recorded. The primary outcome was mortality. Descriptive statistics, Kaplan-Meier (KM) survival analysis, and Cox regression analysis were performed.
    Results: One hundred fourteen patients at 22 medical centers in 6 countries underwent partial resection of an infected aortic graft. Seventy percent were men with median age 70 years. Ninety-seven percent had a history of open aortic bypass graft: 88 (77%) patients had infected aortobifemoral bypass, 18 (16%) had infected aortobiiliac bypass, and 1 (0.8%) had an infected thoracic graft. Infection was diagnosed at a median 4.3 years post-implant. All patients underwent partial resection followed by either extra-anatomic (47%) or in situ (53%) vascular reconstruction. Median follow-up period was 17 months (IQR 1, 50 months). Thirty-day mortality was 17.5%. The KM-estimated median survival from time of partial resection was 3.6 years. There was no significant survival difference between those undergoing in situ reconstruction or extra-anatomic bypass (P = 0.6). During follow up, 72% of repairs remained patent and 11% of patients underwent major amputation. On univariate Cox regression analysis, Candida infection was associated with increased risk of mortality (HR 2.4; P = 0.01) as well as aortoenteric fistula (HR 1.9, P = 0.03). Resection of a single graft limb only to resection of abdominal (graft main body) infection was associated with decreased risk of mortality (HR 0.57, P = 0.04), as well as those with American Society of Anesthesiologists classification less than 3 (HR 0.35, P = 0.04). Multivariate analysis did not reveal any factors significantly associated with mortality. Persistent early infection was noted in 26% of patients within 30 days postoperatively, and 39% of patients were found to have any post-repair infection during the follow-up period. Two patients (1.8%) were found to have a late reinfection without early persistent postoperative infection. Patients with any post-repair infection were older (67 vs. 60 years, P = 0.01) and less likely to have patent repairs during follow up (59% vs. 32%, P = 0.01). Patients with aortoenteric fistula had a higher rate of any post-repair infection (63% vs. 29%, P < 0.01) CONCLUSION: This large multi-center study suggests that patients who have undergone partial resection of infected aortic grafts may be at high risk of death or post-repair infection, especially older patients with abdominal infection not isolated to a single graft limb, or with Candida infection or aortoenteric fistula. Late reinfection correlated strongly with early persistent postoperative infection, raising concern for occult retained infected graft material.
    MeSH term(s) Aged ; Aorta/surgery ; Blood Vessel Prosthesis/adverse effects ; Blood Vessel Prosthesis Implantation/adverse effects ; Blood Vessel Prosthesis Implantation/instrumentation ; Blood Vessel Prosthesis Implantation/mortality ; Device Removal/adverse effects ; Device Removal/mortality ; Endovascular Procedures/adverse effects ; Endovascular Procedures/instrumentation ; Endovascular Procedures/mortality ; Female ; Humans ; Male ; Middle Aged ; Prosthesis-Related Infections/diagnosis ; Prosthesis-Related Infections/microbiology ; Prosthesis-Related Infections/mortality ; Prosthesis-Related Infections/surgery ; Reoperation ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Time Factors
    Language English
    Publishing date 2021-08-23
    Publishing country Netherlands
    Document type Journal Article ; Multicenter Study
    ZDB-ID 1027366-9
    ISSN 1615-5947 ; 0890-5096
    ISSN (online) 1615-5947
    ISSN 0890-5096
    DOI 10.1016/j.avsg.2021.07.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  8. Article ; Online: NCCN molecular testing white paper: effectiveness, efficiency, and reimbursement.

    Engstrom, Paul F / Bloom, Mara G / Demetri, George Daniel / Febbo, Phillip G / Goeckeler, William / Ladanyi, Marc / Loy, Bryan / Murphy, Kate / Nerenberg, Michael / Papagni, Paul / Robson, Mark / Sweetman, Robert W / Tunis, Sean / Demartino, Jessica / Larsen, Jonathan K

    Journal of the National Comprehensive Cancer Network : JNCCN

    2011  Volume 9 Suppl 6, Page(s) S1–16

    Abstract: Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to ... ...

    Abstract Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility from clinical, scientific, and coverage policy standpoints. The NCCN Molecular Testing Work Group identified challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence.
    MeSH term(s) Biomarkers, Tumor/analysis ; Humans ; Medical Oncology/methods ; Medical Oncology/standards ; Medical Oncology/trends ; Molecular Biology/methods ; Molecular Biology/standards ; Molecular Biology/trends ; Neoplasms/diagnosis ; Neoplasms/genetics
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2011-12-22
    Publishing country United States
    Document type Guideline ; Journal Article
    ZDB-ID 2250759-0
    ISSN 1540-1413 ; 1540-1405
    ISSN (online) 1540-1413
    ISSN 1540-1405
    DOI 10.6004/jnccn.2011.0138
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  9. Article: NCCN Oncology Risk Evaluation and Mitigation Strategies White Paper: Recommendations for Stakeholders.

    Johnson, Philip E / Dahlman, George / Eng, Kirby / Garg, Rekha / Gottlieb, Scott / Hoffman, James M / Howell, Peyton / Jahanzeb, Mohammad / Johnson, Shirley / Mackler, Emily / Rubino, Mark / Sarokhan, Brenda / Marc Stewart, F / Tyler, Tim / Vose, Julie M / Weinstein, Sharon / Li, Edward C / Demartino, Jessica

    Journal of the National Comprehensive Cancer Network : JNCCN

    2010  Volume 8 Suppl 7, Page(s) S7–S27

    Abstract: REMS are a particularly important issue for oncology and the National Comprehensive Cancer Network (NCCN). A disproportionate number of drugs with complex REMS are used in patients with cancer or hematologic disorders. REMS policies and processes within ... ...

    Abstract REMS are a particularly important issue for oncology and the National Comprehensive Cancer Network (NCCN). A disproportionate number of drugs with complex REMS are used in patients with cancer or hematologic disorders. REMS policies and processes within oncology may act as a model for other clinical areas. A breadth of experience and access to a wide knowledge base exists within oncology that will ensure appropriate development and consideration of the practical implications of REMS. NCCN is uniquely positioned to assume a leadership role in this process given its status as the arbiter of high-quality cancer care based on its world-leading institutions and clinicians. Notwithstanding the potential benefits, the successful design, implementation, and analysis of the FDA's recent requirement for REMS for some high-risk drugs and biologics will present significant challenges for stakeholders, including patients, providers, cancer centers, manufacturers, payors, health information technology vendors, and regulatory agencies. To provide guidance to these stakeholders regarding REMS challenges, the NCCN assembled a work group comprised of thought leaders from NCCN Member Institutions and other outside experts. The Work Group identified challenges across the REMS spectrum, including the areas of standardization, development and assessment of REMS programs, medication guides, provider knowledge and impact on prescribing, provider burden and compensation, and incorporation of REMS into clinical practice.
    MeSH term(s) Advisory Committees/organization & administration ; Antineoplastic Agents/therapeutic use ; Biological Products/therapeutic use ; Drug Industry/standards ; Drug Industry/trends ; Drug Labeling/standards ; Drug Labeling/trends ; Drug Monitoring/standards ; Drug Monitoring/trends ; Drug Therapy/methods ; Drug Therapy/standards ; Drug Therapy/trends ; Drug-Related Side Effects and Adverse Reactions/prevention & control ; Drugs, Investigational/therapeutic use ; Expert Testimony ; Health Care Surveys ; Health Literacy ; Health Personnel/economics ; Humans ; Interdisciplinary Communication ; Medical Oncology/methods ; Medical Oncology/standards ; Medical Oncology/trends ; Off-Label Use/standards ; Reimbursement Mechanisms ; Risk Assessment/methods ; Risk Assessment/standards ; Risk Assessment/trends ; Safety Management/methods ; Safety Management/standards ; Safety Management/trends ; United States ; United States Food and Drug Administration/legislation & jurisprudence
    Chemical Substances Antineoplastic Agents ; Biological Products ; Drugs, Investigational
    Language English
    Publishing date 2010-10-08
    Publishing country United States
    Document type Guideline ; Journal Article
    ZDB-ID 2250759-0
    ISSN 1540-1405
    ISSN 1540-1405
    DOI 10.6004/jnccn.2010.0135
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  10. Article: Conformational remodeling of proteasomal substrates by PA700, the 19 S regulatory complex of the 26 S proteasome.

    Liu, Chang-Wei / Millen, Linda / Roman, Tracie B / Xiong, Hai / Gilbert, Hiram F / Noiva, Robert / DeMartino, George N / Thomas, Philip J

    The Journal of biological chemistry

    2002  Volume 277, Issue 30, Page(s) 26815–26820

    Abstract: PA700, the 19 S regulatory complex of the 26 S proteasome, plays a central role in the recognition and efficient degradation of misfolded proteins. PA700 promotes degradation by recruiting proteasomal substrates utilizing polyubiquitin chains and ... ...

    Abstract PA700, the 19 S regulatory complex of the 26 S proteasome, plays a central role in the recognition and efficient degradation of misfolded proteins. PA700 promotes degradation by recruiting proteasomal substrates utilizing polyubiquitin chains and chaperone-like binding activities and by opening the access to the core of the 20 S proteasome to promote degradation. Here we provide evidence that PA700 in addition to binding misfolded protein substrates also acts to remodel their conformation prior to proteolysis. Scrambled RNase A (scRNase A), a misfolded protein, only slowly refolds spontaneously into an active form because of the rate-limiting unfolding of misfolded disulfide isomers. Notably, PA700 accelerates the rate of reactivation of scRNase A, consistent with its ability to increase the exposure of these disulfide bonds to the solvent. In this regard, PA700 also exposes otherwise buried sites to digestion by exogenous chymotrypsin in a polyubiquitinated enzymatically active substrate, pentaubiquitinated dihydrofolate reductase, Ub(5)DHFR. The dihydrofolate reductase ligand methotrexate counters the ability of PA700 to promote digestion by chymotrypsin. Together, these results indicate that in addition to increasing substrate affinity and opening the access channel to the catalytic sites, PA700 activates proteasomal degradation by remodeling the conformation of protein substrates.
    MeSH term(s) Adenosine Triphosphatases/chemistry ; Animals ; Catalytic Domain ; Cattle ; Chymotrypsin/pharmacology ; Disulfides/chemistry ; Dose-Response Relationship, Drug ; Endopeptidases/chemistry ; Enzyme Inhibitors/pharmacology ; Ligands ; Methotrexate/pharmacology ; Oxygen/metabolism ; Peptides/chemistry ; Proteasome Endopeptidase Complex ; Protein Conformation ; Protein Folding ; Ribonuclease, Pancreatic/chemistry ; Time Factors
    Chemical Substances Disulfides ; Enzyme Inhibitors ; Ligands ; Peptides ; Ribonuclease, Pancreatic (EC 3.1.27.5) ; Endopeptidases (EC 3.4.-) ; Chymotrypsin (EC 3.4.21.1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; 26S proteasome non-ATPase regulatory subunit 13 (EC 3.6.1.-) ; Adenosine Triphosphatases (EC 3.6.1.-) ; Oxygen (S88TT14065) ; Methotrexate (YL5FZ2Y5U1)
    Language English
    Publishing date 2002-05-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M201782200
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

To top