274 results on '"Alan L. Schwartz"'
Search Results
2. RNF4-Dependent Oncogene Activation by Protein Stabilization
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Jane J. Thomas, Mona Abed, Julian Heuberger, Rostislav Novak, Yaniv Zohar, Angela P. Beltran Lopez, Julie S. Trausch-Azar, Ma. Xenia G. Ilagan, David Benhamou, Gunnar Dittmar, Raphael Kopan, Walter Birchmeier, Alan L. Schwartz, and Amir Orian
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STUbL ,ubiquitin ,SUMO ,gene regulation ,oncogenes ,Biology (General) ,QH301-705.5 - Abstract
Ubiquitylation regulates signaling pathways critical for cancer development and, in many cases, targets proteins for degradation. Here, we report that ubiquitylation by RNF4 stabilizes otherwise short-lived oncogenic transcription factors, including β-catenin, Myc, c-Jun, and the Notch intracellular-domain (N-ICD) protein. RNF4 enhances the transcriptional activity of these factors, as well as Wnt- and Notch-dependent gene expression. While RNF4 is a SUMO-targeted ubiquitin ligase, protein stabilization requires the substrate’s phosphorylation, rather than SUMOylation, and binding to RNF4’s arginine-rich motif domain. Stabilization also involves generation of unusual polyubiquitin chains and docking of RNF4 to chromatin. Biologically, RNF4 enhances the tumor phenotype and is essential for cancer cell survival. High levels of RNF4 mRNA correlate with poor survival of a subgroup of breast cancer patients, and RNF4 protein levels are elevated in 30% of human colon adenocarcinomas. Thus, RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation.
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- 2016
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3. Degradation of the LDL receptor class 2 mutants is mediated by a proteasome-dependent pathway
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Yonghe Li, Wenyan Lu, Alan L. Schwartz, and Guojun Bu
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familial hypercholesterolemia ,mutation ,degradation ,Biochemistry ,QD415-436 - Abstract
Familial hypercholesterolemia is a genetic disorder that results from various gene mutations, primarily within the LDL receptor (LDLR). Approximately 50% of the LDLR mutations are defined as class 2 mutations, with the mutant proteins partially or entirely retained in the endoplasmic reticulum. To determine the degradation pathway of the LDLR class 2 mutants, we examined the effects of inhibition of several potential pathways on the levels of the wild-type LDLR and its four representative class 2 mutants (S156L, C176Y, E207K, and C646Y) stably expressed in Chinese hamster ovary (CHO) cells. We found that proteasome inhibitors MG132 and lactacystin blocked the degradation of the LDLR mutants, but not that of the wild-type LDLR. Treatment of CHO cells with these proteasome inhibitors led to a significant accumulation of the mutants at steady state. Furthermore, cell surface levels of the LDLR mutants were significantly increased upon inhibition of the proteasome degradation pathway. In contrast to the proteasome inhibitors, inhibitors of trypsin-like proteases, chymotrypsin-like proteases, and lysosomal pathway inhibitors did not affect the levels of the LDLR mutants.Taken together, these data demonstrate that the proteasome is the principal degradation pathway for LDLR class 2 mutants.
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- 2004
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4. The Future of Children’s Health in the Genomic Era
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Alan L. Schwartz
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Genomics ,bioinformatics ,microbiome ,genetics ,child/children ,pediatrics ,Medicine ,Medicine (General) ,R5-920 - Abstract
The effects of genomic medicine on child health promise to be profound. Medical applications will eventually include characterizing patients’ genomes to detect predictive mutations for pre-symptomatic counseling where treatment exists; to search for causes of diseases of unknown etiology, and to detect carriers for prenatal counseling; to define cancer and other disease-based genomes to design individualized therapy; and to understand our microbiomes to modify these in health and disease. Rapid advances in technology and bioinformatics have reduced the cost and the time and increased the accuracy necessary to sequence whole genomes or whole exomes. However, complete understanding of disease will also require correlation of genomic information with high-quality phenotypic data. In addition, several critical ethical, psycho-social, and public policy issues will require clarity in the coming years. Ultimately these advances will improve the effectiveness of health care for children and for society.
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- 2011
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5. Electromyometrial Imaging of Uterine Contractions in Pregnant Women
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Hui Wang, Zichao Wen, Wenjie Wu, Zhexian Sun, Qing Wang, Alan L. Schwartz, Phillip Cuculich, Alison G. Cahill, George A. Macones, and Yong Wang
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General Immunology and Microbiology ,General Chemical Engineering ,General Neuroscience ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
6. Supplementary Video 1 from Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
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Guojun Bu, Alan L. Schwartz, Jiyeon Lee, Yonghe Li, and Heesang Song
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Supplementary Video 1 from Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
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- 2023
7. Supplementary Methods and Materials, Figures 1-3 from Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
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Guojun Bu, Alan L. Schwartz, Jiyeon Lee, Yonghe Li, and Heesang Song
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Supplementary Methods and Materials, Figures 1-3 from Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
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- 2023
8. Supplementary Video 2 from Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
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Guojun Bu, Alan L. Schwartz, Jiyeon Lee, Yonghe Li, and Heesang Song
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Supplementary Video 2 from Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
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- 2023
9. Data from Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
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Guojun Bu, Alan L. Schwartz, Jiyeon Lee, Yonghe Li, and Heesang Song
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The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor involved in the metabolism of various extracellular ligands, including proteinases, that play critical roles in tumor invasion. Although several studies have shown an increased expression of LRP1 in cancer cells, its function in tumor development and progression remains largely unclear. Here, we reveal a novel mechanism by which LRP1 induces the expression of matrix metalloproteinase 2 (MMP2) and MMP9 and thereby promotes the migration and invasion of human glioblastoma U87 cells. Knockdown of LRP1 expression greatly decreased U87 cell migration and invasion, which was rescued by the forced expression of a functional LRP1 minireceptor. Inhibition of ligand binding to LRP1 by a specific antagonist, receptor-associated protein, also led to reduced cancer cell migration and invasion. Because MMPs play critical roles in cancer cell migration and invasion, we examined the expression of several MMPs and found that the expression of functional MMP2 and MMP9 was selectively decreased in LRP1 knockdown cells. More importantly, decreased cell migration and invasion of LRP1 knockdown cells were completely rescued by exogenous expression of MMP2 or MMP9, suggesting that these MMPs are likely downstream targets of LRP1-mediated signaling. We further show that the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in LRP1-silenced cells, suggesting that ERK is a potential mediator of LRP1-regulated MMP2 and MMP9 expression in U87 cells. Together, our data strongly suggest that LRP1 promotes glioblastoma cell migration and invasion by regulating the expression and function of MMP2 and MMP9 perhaps via an ERK-dependent signaling pathway. [Cancer Res 2009;69(3):879–86]
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- 2023
10. Accuracy of electromyometrial imaging of uterine contractions in clinical environment.
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Hui Wang, Wenjie Wu, Michael Talcott, Robert C. McKinstry, Pamela K. Woodard, George A. Macones, Alan L. Schwartz, Phillip Cuculich, Alison G. Cahill, and Yong Wang
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- 2020
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11. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population
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David B. Beck, Dale L. Bodian, Vandan Shah, Uyenlinh L. Mirshahi, Jung Kim, Yi Ding, Samuel J. Magaziner, Natasha T. Strande, Anna Cantor, Jeremy S. Haley, Adam Cook, Wesley Hill, Alan L. Schwartz, Peter C. Grayson, Marcela A. Ferrada, Daniel L. Kastner, David J. Carey, and Douglas R. Stewart
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General Medicine - Abstract
ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes.ObjectiveTo determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.Design, Setting, and ParticipantsThis retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022.ExposuresExome sequencing was performed.Main Outcomes and MeasuresOutcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.ResultsIn 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).Conclusions and RelevanceThis study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.
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- 2023
12. A multidisciplinary Prematurity Research Cohort Study
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Yong Wang, George A. Macones, Sarah K. England, Justin C. Fay, Molly J. Stout, Lihong V. Wang, Alison G. Cahill, Jessica Chubiz, Nandini Raghuraman, Erik D. Herzog, Phillip S. Cuculich, Alan L. Schwartz, Peinan Zhao, Methodius G. Tuuli, and Emily S. Jungheim
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Longitudinal study ,medicine.medical_specialty ,Maternal blood ,Cohort Studies ,Pregnancy ,medicine ,Humans ,Longitudinal Studies ,Prospective Studies ,Multidisciplinary ,medicine.diagnostic_test ,Obstetrics ,business.industry ,Infant, Newborn ,Infant ,Magnetic resonance imaging ,Infant, Low Birth Weight ,medicine.disease ,Cohort ,Gestation ,Premature Birth ,Female ,business ,Live birth ,Cohort study - Abstract
Background Worldwide, 10% of babies are born preterm, defined as a live birth before 37 weeks of gestation. Preterm birth is the leading cause of neonatal death, and survivors face lifelong risks of adverse outcomes. New approaches with large sample sizes are needed to identify strategies to predict and prevent preterm birth. The primary aims of the Washington University Prematurity Research Cohort Study were to conduct three prospective projects addressing possible causes of preterm birth and provide data and samples for future research. Study design Pregnant patients were recruited into the cohort between January 2017 and January 2020. Consenting patients were enrolled into the study before 20 weeks’ gestation and followed through delivery. Participants completed demographic and lifestyle surveys; provided maternal blood, placenta samples, and cord blood; and participated in up to three projects focused on underlying physiology of preterm birth: cervical imaging (Project 1), circadian rhythms (Project 2), and uterine magnetic resonance imaging and electromyometrial imaging (Project 3). Results A total of 1260 participants were enrolled and delivered during the study period. Of the participants, 706 (56%) were Black/African American, 494 (39%) were nulliparous, and 185 (15%) had a previous preterm birth. Of the 1260 participants, 1220 (97%) delivered a live infant. Of the 1220 with a live birth, 163 (14.1%) had preterm birth, of which 74 (6.1%) were spontaneous preterm birth. Of the 1220 participants with a live birth, 841 participated in cervical imaging, 1047 contributed data and/or samples on circadian rhythms, and 39 underwent uterine magnetic resonance imaging. Of the 39, 25 underwent electromyometrial imaging. Conclusion We demonstrate feasibility of recruiting and retaining a diverse cohort in a complex prospective, longitudinal study throughout pregnancy. The extensive clinical, imaging, survey, and biologic data obtained will be used to explore cervical, uterine, and endocrine physiology of preterm birth and can be used to develop novel approaches to predict and prevent preterm birth.
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- 2022
13. Partial Differential Equations and Bivariate Orthogonal Polynomials.
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Alan L. Schwartz
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- 1999
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14. Analysis of Electrophysiological Activation of the Uterus During Human Labor Contractions
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Alison G, Cahill, Zichao, Wen, Hui, Wang, Peinan, Zhao, Zhexian, Sun, Alan L, Schwartz, and Yong, Wang
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Uterine Contraction ,Pregnancy ,Uterus ,Humans ,Female ,General Medicine ,Electrophysiological Phenomena - Published
- 2022
15. RNA‐Seq identifies genes whose proteins are upregulated during syncytia development in murine C2C12 myoblasts and human BeWo trophoblasts
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Alan L. Schwartz, Julie S. Trausch-Azar, D. Michael Nelson, C G Azar, Lisa E. Rois, Mark C. Valentine, and Moe R. Mahjoub
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placenta ,Physiology ,030204 cardiovascular system & hematology ,Biology ,Giant Cells ,Myoblasts ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Syncytiotrophoblast ,Pregnancy ,Physiology (medical) ,Placenta ,syncytialization ,Gene expression ,medicine ,Animals ,Humans ,RNA-Seq ,Gene ,Cells, Cultured ,reproductive and urinary physiology ,Original Research ,Syncytium ,cell fusion ,Cytotrophoblast ,Trophoblasts ,Cell biology ,medicine.anatomical_structure ,embryonic structures ,Female ,Cytotrophoblasts ,C2C12 ,030217 neurology & neurosurgery - Abstract
The fusion of villous cytotrophoblasts into the multinucleated syncytiotrophoblast is critical for the essential functions of the mammalian placenta. Using RNA‐Seq gene expression, quantitative protein expression, and siRNA knockdown we identified genes and their cognate proteins which are similarly upregulated in two cellular models of mammalian syncytia development (human BeWo cytotrophoblast to syncytiotrophoblast and murine C2C12 myoblast to myotube). These include DYSF, PDE4DIP, SPIRE2, NDRG1, PLEC, GPR146, HSPB8, DHCR7, and HDAC5. These findings provide avenues for further understanding of the mechanisms underlying mammalian placental syncytiotrophoblast development., The fusion of villous cytotrophoblasts into the multinucleated syncytiotrophoblast is critical for the essential functions of the mammalian placenta. Using RNA‐Seq gene expression, quantitative protein expression, and siRNA knockdown we identified genes and their cognate proteins which are similarly up‐regulated in two cellular models of mammalian syncytia development (human BeWo cytotrophoblast to syncytiotrophoblast and murine C2C12 myoblast to myotube). These include DYSF, PDE4DIP, SPIRE2, NDRG1, PLEC, GPR146, HSPB8, DHCR7, and HDAC5.
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- 2021
16. Simple questions with complex answers
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David J. York and Alan L. Schwartz
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Computer science ,Simple (abstract algebra) ,Calculus - Published
- 2020
17. Addressing Gaps in Pediatric Scientist Development: The Department Chair View of 2 AMSPDC-Sponsored Programs
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Margaret K. Hostetter, Katherine J. Barrett, T. Michelle Cooley, Sallie R. Permar, D. Wade Clapp, and Alan L. Schwartz
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Medical education ,Biomedical Research ,business.industry ,Pediatrics, Perinatology and Child Health ,education ,MEDLINE ,Medicine ,business ,Pediatrics ,health care economics and organizations ,humanities ,United States ,Article - Abstract
Pediatric physician-scientists are important members of the biomedical workforce who are instrumental in translating research advances into novel patient treatment strategies, yet their numbers have been declining over the past four decades. In order to increase the pipeline of pediatric physician-scientists, the Association of Medical School Pediatric Department Chairs (AMSPDC) leads the Frontiers in Science (FIS) and Pediatric Scientist Development Program (PSDP). These programs provide mentorship, networking, and funding opportunities for pediatric residents and fellows who are interested in pursuing research careers. To assess perceptions of program accessibility and efficacy, FIS and PSDP leadership surveyed AMSPDC membership between November 2018 and April 2019; 66 active department chairs responded. The decline in pediatric physician-scientists was identified as a common concern, and responding chairs identified several individual and institutional barriers to the physician-scientist career pathway and to participation in FIS and PSDP. Common barriers to participation included: undefined career paths for physician-scientists, a limited number of FIS slots annually, a perception that these programs support primarily basic science rather than other types of research, and competing funding through institutional T32 and K12 programs. To address these barriers, FIS and PSDP leadership will work with AMSPDC to explore ways to increase access to FIS, promote PSDP alumni mentoring of participating residents and fellows, and expand the scope of research supported by these programs. Assessments of FIS and PSDP will be ongoing, with the goal of improving program access in order to increase and diversify the pediatric physician-scientist workforce.
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- 2020
18. Electromyometrial imaging dataset of electromyograms and isochrone maps under deformation/electrical noise contaminations
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Yong Wang, Alison G. Cahill, Robert C. McKinstry, Alan L. Schwartz, Phillip S. Cuculich, Pamela K. Woodard, Wenjie Wu, Michael Talcott, George A. Macones, and Hui Wang
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0303 health sciences ,Multidisciplinary ,medicine.diagnostic_test ,business.industry ,Geometry ,Magnetic resonance imaging ,Sheep model ,Deformation (meteorology) ,Electrical noise ,03 medical and health sciences ,Isochrone maps ,0302 clinical medicine ,Engineering ,Electromyometrial imaging ,Electrocardiographic imaging ,medicine ,Computer vision ,Artificial intelligence ,Electromyograms ,business ,030217 neurology & neurosurgery ,Geology ,030304 developmental biology - Abstract
The dataset presented in this paper is related to the recent work "Accuracy of electromyometrial imaging of uterine contractions in clinical environment" [1]. The dataset including body-uterus geometry obtained from magnetic resonance imaging (MRI), uterine electrograms and isochrone maps reconstructed using Electromyometrial imaging (EMMI) under various levels of deformations and electrical noise contamination in a translational sheep model are reported. The dataset make it possible for detailed evaluation and further improvement of EMMI. In addition, the researchers working on other types of electrophysiology imaging techniques, such as electrocardiographic imaging (ECGI), and Electrogastrography imaging (EGGI) could also adopt our method [1] and employ the dataset to evaluate and improve their imaging techniques.
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- 2019
19. Accuracy of electromyometrial imaging of uterine contractions in clinical environment
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Robert C. McKinstry, Alison G. Cahill, George A. Macones, Michael Talcott, Wenjie Wu, Phillip S. Cuculich, Hui Wang, Alan L. Schwartz, Pamela K. Woodard, and Yong Wang
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0301 basic medicine ,Diagnostic Imaging ,Uterine surface ,Health Informatics ,Electromyography ,Article ,03 medical and health sciences ,Uterine Contraction ,0302 clinical medicine ,Pregnancy ,Abdomen ,medicine ,Image Processing, Computer-Assisted ,Animals ,Preterm delivery ,Monitoring, Physiologic ,Sheep ,medicine.diagnostic_test ,business.industry ,Uterus ,Magnetic resonance imaging ,Signal Processing, Computer-Assisted ,Computer Science Applications ,Electrophysiology ,030104 developmental biology ,Female ,business ,Research setting ,030217 neurology & neurosurgery ,Biomedical engineering - Abstract
Clinically, uterine contractions are monitored with tocodynamometers or intrauterine pressure catheters. In the research setting, electromyography (EMG), which detects electrical activity of the uterus from a few electrodes on the abdomen, is feasible, can provide more accurate data than these other methods, and may be useful for predicting preterm birth. However, EMG lacks sufficient spatial resolution and coverage to reveal where uterine contractions originate, how they propagate, and whether preterm contractions differ between women who do and do not progress to preterm delivery. To address those limitations, electromyometrial imaging (EMMI) was recently developed and validated to non-invasively assess three-dimensional (3D) electrical activation patterns on the entire uterine surface in pregnant sheep. EMMI uses magnetic resonance imaging to obtain subject-specific body-uterus geometry and collects uterine EMG data from up to 256 electrodes on the body surface. EMMI software then solves an ill-posed inverse computation to combine the two datasets and generate maps of electrical activity on the entire 3D uterine surface. Here, we assessed the feasibility to clinically translate EMMI by evaluating EMMI's accuracy under the unavoidable geometrical alterations and electrical noise contamination in a clinical environment. We developed a hybrid experimental-simulation platform to model the effects of fetal kicks, contractions, fetal/maternal movements, and noise contamination caused by maternal respiration and environmental electrical activity. Our data indicate that EMMI can accurately image uterine electrical activity in the presence of geometrical deformations and electrical noise, suggesting that EMMI can be reliably translated to non-invasively image 3D uterine electrical activation in pregnant women.
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- 2019
20. Noninvasive high-resolution electromyometrial imaging of uterine contractions in a translational sheep model
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Alan L. Schwartz, Phillip S. Cuculich, Peinan Zhao, Robert C. McKinstry, Yong Wang, Shengsheng Lai, Hui Wang, Alison G. Cahill, Wenjie Wu, George A. Macones, Pamela K. Woodard, and Michael Talcott
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0301 basic medicine ,Materials science ,Uterine surface ,High resolution ,Electromyography ,Oxytocin ,Translational Research, Biomedical ,03 medical and health sciences ,Uterine Contraction ,0302 clinical medicine ,medicine ,Animals ,Tocodynamometer ,030219 obstetrics & reproductive medicine ,Sheep ,medicine.diagnostic_test ,Magnetic resonance imaging ,General Medicine ,Magnetic Resonance Imaging ,Clinical Practice ,030104 developmental biology ,Intrauterine pressure catheter ,Temporal resolution ,Models, Animal ,Myometrium ,Feasibility Studies ,Female ,Biomedical engineering - Abstract
In current clinical practice, uterine contractions are monitored via a tocodynamometer or an intrauterine pressure catheter, both of which provide crude information about contractions. Although electrohysterography/electromyography can measure uterine electrical activity, this method lacks spatial specificity and thus cannot accurately measure the exact location of electrical initiation and location-specific propagation patterns of uterine contractions. To comprehensively evaluate three-dimensional uterine electrical activation patterns, we describe here the development of electromyometrial imaging (EMMI) to display the three-dimensional uterine contractions at high spatial and temporal resolution. EMMI combines detailed body surface electrical recording with body-uterus geometry derived from magnetic resonance images. We used a sheep model to show that EMMI can reconstruct uterine electrical activation patterns from electrodes placed on the abdomen. These patterns closely match those measured with electrodes placed directly on the uterine surface. In addition, modeling experiments showed that EMMI reconstructions are minimally affected by noise and geometrical deformation. Last, we show that EMMI can be used to noninvasively measure uterine contractions in sheep in the same setup as would be used in humans. Our results indicate that EMMI can noninvasively, safely, accurately, robustly, and feasibly image three-dimensional uterine electrical activation during contractions in sheep and suggest that similar results might be obtained in clinical setting.
- Published
- 2018
21. Third-Party Beneficiaries and Contractual Networks
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Alan L. Schwartz and Robert E. Scott
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Breach of contract ,Principal (commercial law) ,Third party ,Ask price ,media_common.quotation_subject ,Honor ,Damages ,Beneficiary ,Doctrine ,Business ,Law ,Law and economics ,media_common - Abstract
An increasing trend of economic agents is to form productive associations such as networks, platforms, and other hybrids. Subsets of these agents contract with each other to further their network project and these contracts can create benefits for, or impose costs on, agents who are not contract parties. Contract law regulates third party claims against contract parties with the third-party beneficiary doctrine, which directs courts to ask whether the contracting parties “intended” to benefit a particular third party. We show here what courts do with third party claims when network members fail to perform for third parties and what the law’s best responses to such breaches should be. Among our principal results are that courts honor third party claims when contract members likely can price them and when third parties incur substantial reliance losses, but protect thirdparty interests less frequently than they should and refuse relief when contract members can identify the potential beneficiary class but not every agent who is likely to be in it.
- Published
- 2015
22. Isoform-Specific SCFFbw7Ubiquitination Mediates Differential Regulation of PGC-1α
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Julie S. Trausch-Azar, Amir Orian, Mona Abed, and Alan L. Schwartz
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Gene isoform ,biology ,Physiology ,Clinical Biochemistry ,Cell Biology ,F-box protein ,Ubiquitin ligase ,Cell biology ,Ubiquitin ,Coactivator ,biology.protein ,Phosphorylation ,Cell Cycle Protein ,Transcription factor - Abstract
The E3 ubiquitin ligase and tumor suppressor SCFFbw7 exists as three isoforms that govern the degradation of a host of critical cell regulators, including c-Myc, cyclin E, and PGC-1α. Peroxisome proliferator activated receptor-gamma coactivator 1α (PGC-1α) is a transcriptional coactivator with broad effects on cellular energy metabolism. Cellular PGC-1α levels are tightly controlled in a dynamic state by the balance of synthesis and rapid degradation via the ubiquitin-proteasome system. Yet, isoform-specific functions of SCFFbw7 are yet to be determined. Here, we show that the E3 ubiquitin ligase, SCFFbw7, regulates cellular PGC-1α levels via two independent, isoform specific, mechanisms. The cytoplasmic isoform (SCFFbw7β) reduces cellular PGC-1α levels via accelerated ubiquitin-proteasome degradation. In contrast, the nuclear isoform (SCFFbw7α) increases cellular PGC-1α levels and protein stability via inhibition of ubiquitin-proteasomal degradation. When nuclear Fbw7α proteins are redirected to the cytoplasm, cellular PGC-1α protein levels are reduced through accelerated ubiquitin-proteasomal degradation. We find that SCFFbw7β catalyzes high molecular weight PGC-1α-ubiquitin conjugation, whereas SCFFbw7α produces low molecular weight PGC-1α-ubiquitin conjugates that are not effective degradation signals. Thus, selective ubiquitination by specific Fbw7 isoforms represents a novel mechanism that tightly regulates cellular PGC-1α levels. Fbw7 isoforms mediate degradation of a host of regulatory proteins. The E3 ubiquitin ligase, Fbw7, mediates PGC-1α levels via selective isoform-specific ubiquitination. Fbw7β reduces cellular PGC-1α via ubiquitin-mediated degradation, whereas Fbw7α increases cellular PGC-1α via ubiquitin-mediated stabilization.
- Published
- 2014
23. American Pediatric Society 2014 presidential address: the thrill of discovery (and other foundations of biomedical research)
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Alan L. Schwartz
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Biomedical Research ,Career Choice ,Universities ,Cost-Benefit Analysis ,History, 19th Century ,History, 20th Century ,History, 21st Century ,Pediatrics ,Research Personnel ,Research Support as Topic ,Political science ,Presidential address ,Pediatrics, Perinatology and Child Health ,Animals ,Humans ,Engineering ethics ,Diffusion of Innovation ,Forecasting - Abstract
American Pediatric Society 2014 presidential address: the thrill of discovery (and other foundations of biomedical research)
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- 2014
24. RNF4-dependent oncogene activation by protein stabilization
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Yaniv Zohar, Alan L. Schwartz, Julie S. Trausch-Azar, Raphael Kopan, Gunnar Dittmar, Walter Birchmeier, Amir Orian, Ángela Patricia Beltrán López, Ma. Xenia G. Ilagan, David Benhamou, Mona Abed, Jane Joy Thomas, Rostislav Novak, and Julian Heuberger
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0301 basic medicine ,Cancer Research ,SUMO protein ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,ubiquitin ,Humans ,Nuclear protein ,Transcription factor ,lcsh:QH301-705.5 ,biology ,RNF4 ,Protein Stability ,Wnt signaling pathway ,Ubiquitination ,Nuclear Proteins ,Oncogenes ,3. Good health ,Ubiquitin ligase ,030104 developmental biology ,STUbL ,lcsh:Biology (General) ,SUMO ,biology.protein ,Cancer research ,Phosphorylation ,Protein stabilization ,Technology Platforms ,gene regulation ,Transcription Factors - Abstract
SUMMARY Ubiquitylation regulates signaling pathways critical for cancer development and, in many cases, targets proteins for degradation. Here, we report that ubiquitylation by RNF4 stabilizes otherwise short-lived oncogenic transcription factors, including β-catenin, Myc, c-Jun, and the Notch intracellular-domain (N-ICD) protein. RNF4 enhances the transcriptional activity of these factors, as well as Wnt- and Notch-dependent gene expression. While RNF4 is a SUMO-targeted ubiquitin ligase, protein stabilization requires the substrate’s phosphorylation, rather than SUMOylation, and binding to RNF4’s arginine-rich motif domain. Stabilization also involves generation of unusual polyubiquitin chains and docking of RNF4 to chromatin. Biologically, RNF4 enhances the tumor phenotype and is essential for cancer cell survival. High levels of RNF4 mRNA correlate with poor survival of a subgroup of breast cancer patients, and RNF4 protein levels are elevated in 30% of human colon adenocarcinomas. Thus, RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation., Graphical Abstract
- Published
- 2016
25. 11. Mentoring the Physician-Scientist: A Developmental Approach
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Alan L. Schwartz and Margaret K. Hostetter
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Medical education ,Physician-scientist ,Developmental approach ,Psychology - Published
- 2016
26. Ubiquitin Proteasome-dependent Degradation of the Transcriptional Coactivator PGC-1α via the N-terminal Pathway
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Julie S. Trausch-Azar, Teresa C. Leone, Daniel P. Kelly, and Alan L. Schwartz
- Subjects
Cytoplasm ,Proteasome Endopeptidase Complex ,Biology ,Protein degradation ,Biochemistry ,Mice ,Ubiquitin ,Transcriptional regulation ,Animals ,Humans ,Amino Acid Sequence ,Molecular Biology ,Transcription factor ,Heat-Shock Proteins ,Cellular localization ,Sequence Deletion ,Cell Nucleus ,Protein Stability ,Hep G2 Cells ,Cell Biology ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Protein Structure, Tertiary ,Ubiquitin ligase ,Mitochondrial biogenesis ,Proteasome ,Protein Synthesis and Degradation ,Trans-Activators ,biology.protein ,HeLa Cells ,Transcription Factors - Abstract
PGC-1α is a potent, inducible transcriptional coactivator that exerts control on mitochondrial biogenesis and multiple cellular energy metabolic pathways. PGC-1α levels are controlled in a highly dynamic manner reflecting regulation at both transcriptional and post-transcriptional levels. Here, we demonstrate that PGC-1α is rapidly degraded in the nucleus (t(½ 0.3 h) via the ubiquitin proteasome system. An N-terminal deletion mutant of 182 residues, PGC182, as well as a lysine-less mutant form, are nuclear and rapidly degraded (t(½) 0.5 h), consistent with degradation via the N terminus-dependent ubiquitin subpathway. Both PGC-1α and PGC182 degradation rates are increased in cells under low serum conditions. However, a naturally occurring N-terminal splice variant of 270 residues, NT-PGC-1α is cytoplasmic and stable (t(½7 h), providing additional evidence that PGC-1α is degraded in the nucleus. These results strongly suggest that the nuclear N terminus-dependent ubiquitin proteasome pathway governs PGC-1α cellular degradation. In contrast, the cellular localization of NT-PCG-1α results in a longer-half-life and possible distinct temporal and potentially biological actions.
- Published
- 2010
27. Physician-Scientist Career Awards and a Dilemma
- Author
-
Alan L. Schwartz
- Subjects
Dilemma ,03 medical and health sciences ,Medical education ,0302 clinical medicine ,business.industry ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,Medicine ,030212 general & internal medicine ,business ,Child health ,Human development (humanity) - Published
- 2018
28. Low-Density Lipoprotein Receptor-Related Protein 1 Promotes Cancer Cell Migration and Invasion by Inducing the Expression of Matrix Metalloproteinases 2 and 9
- Author
-
Alan L. Schwartz, Guojun Bu, Jiyeon Lee, Yonghe Li, and Heesang Song
- Subjects
MAPK/ERK pathway ,Cancer Research ,Biology ,Matrix metalloproteinase ,Ligands ,Transfection ,Article ,Cell Movement ,Cell Line, Tumor ,Humans ,Neoplasm Invasiveness ,RNA, Small Interfering ,Extracellular Signal-Regulated MAP Kinases ,Gene knockdown ,Cell migration ,LRP1 ,Up-Regulation ,Cell biology ,Matrix Metalloproteinase 9 ,Oncology ,Cell culture ,Enzyme Induction ,Cancer cell ,Matrix Metalloproteinase 2 ,Signal transduction ,Glioblastoma ,Low Density Lipoprotein Receptor-Related Protein-1 - Abstract
The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor involved in the metabolism of various extracellular ligands, including proteinases, that play critical roles in tumor invasion. Although several studies have shown an increased expression of LRP1 in cancer cells, its function in tumor development and progression remains largely unclear. Here, we reveal a novel mechanism by which LRP1 induces the expression of matrix metalloproteinase 2 (MMP2) and MMP9 and thereby promotes the migration and invasion of human glioblastoma U87 cells. Knockdown of LRP1 expression greatly decreased U87 cell migration and invasion, which was rescued by the forced expression of a functional LRP1 minireceptor. Inhibition of ligand binding to LRP1 by a specific antagonist, receptor-associated protein, also led to reduced cancer cell migration and invasion. Because MMPs play critical roles in cancer cell migration and invasion, we examined the expression of several MMPs and found that the expression of functional MMP2 and MMP9 was selectively decreased in LRP1 knockdown cells. More importantly, decreased cell migration and invasion of LRP1 knockdown cells were completely rescued by exogenous expression of MMP2 or MMP9, suggesting that these MMPs are likely downstream targets of LRP1-mediated signaling. We further show that the level of phosphorylated extracellular signal-regulated kinase (ERK) was significantly decreased in LRP1-silenced cells, suggesting that ERK is a potential mediator of LRP1-regulated MMP2 and MMP9 expression in U87 cells. Together, our data strongly suggest that LRP1 promotes glioblastoma cell migration and invasion by regulating the expression and function of MMP2 and MMP9 perhaps via an ERK-dependent signaling pathway. [Cancer Res 2009;69(3):879–86]
- Published
- 2009
29. The N-terminal domain of MyoD is necessary and sufficient for its nuclear localization-dependent degradation by the ubiquitin system
- Author
-
Muhammad Zoabi, Yelena Kravtsova-Ivantsiv, Beatrice Bercovich, Aaron Ciechanover, Ronen Sadeh, Daniel Kornitzer, Kristin Breitschopf, and Alan L. Schwartz
- Subjects
Cell Nucleus ,Multidisciplinary ,Ubiquitin ,Lysine ,Saccharomyces cerevisiae ,Biological Sciences ,Biology ,biology.organism_classification ,MyoD ,Protein Structure, Tertiary ,Ubiquitin ligase ,Cell biology ,Mice ,Protein structure ,MyoD Protein ,Biochemistry ,biology.protein ,Animals ,Transcription factor ,Conserved Sequence ,Nuclear localization sequence - Abstract
A growing number of proteins, including the myogenic transcription factor MyoD, are targeted for proteasomal degradation after N-terminal ubiquitination (NTU) where the first ubiquitin moiety is conjugated to the N-terminal residue rather than to an internal lysine. NTU might be essential in targeting both lysine-containing and naturally occurring lysine-less proteins such as p16 INK4a and p14 ARF ; however, the mechanisms that underlie this process are largely unknown. Specifically, the recognition motif(s) in the target substrates and the ubiquitin ligase(s) that catalyze NTU are still obscure. Here we show that the N-terminal domain of MyoD is critical for its degradation and that its destabilizing effect depends on nuclear localization of the protein. Deletion of the first 15 aa of MyoD blocked completely its lysine-independent degradation. Importantly, transfer of the first 30 N-terminal residues of MyoD to GFP destabilized this otherwise stable protein, and, here too, targeting for degradation depended on localization of the protein to the nucleus. Deletion of the N-terminal domain of lysine-less MyoD did not abolish completely ubiquitination of the protein, suggesting that this domain may be required for targeting the protein also in a postubiquitination step. Interestingly, NTU is evolutionarily conserved: in the yeast Saccharomyces cerevisiae lysine-less (LL) MyoD is degraded in a ubiquitin-, N-terminal domain-, and nuclear localization-dependent manner. Taken together, our data suggest that a short N-terminal segment of MyoD is necessary and sufficient to render MyoD susceptible for ubiquitin- and nuclear-dependent degradation.
- Published
- 2008
30. Slow endocytosis of the LDL receptor-related protein 1B: Implications for a novel cytoplasmic tail conformation
- Author
-
Alan L. Schwartz, Yonghe Li, Jane M. Knisely, Janice Griffith, Guojun Bu, and Hans J. Geuze
- Subjects
Cytoplasm ,Protein Conformation ,media_common.quotation_subject ,LRP1B ,Molecular Sequence Data ,Endocytic cycle ,CHO Cells ,Biology ,Endocytosis ,Article ,Mice ,Cricetulus ,Protein structure ,Cricetinae ,Animals ,Humans ,Amino Acid Sequence ,Internalization ,media_common ,Tumor Suppressor Proteins ,Cell Biology ,Receptor-mediated endocytosis ,LRP1 ,Cell biology ,Receptors, LDL ,Biochemistry ,Mutation ,LDL receptor ,Low Density Lipoprotein Receptor-Related Protein-1 - Abstract
The LDL receptor-related protein 1B (LRP1B) is a putative tumor suppressor homologous to LRP1. Both LRP1 and LRP1B contain cytoplasmic tails with several potential endocytosis motifs. Although the positions of these endocytic motifs are similar in both receptors, LRP1B is internalized at a 15-fold slower rate than LRP1. To determine whether the slow endocytosis of LRP1B is due to the utilization of an endocytosis motif other than the YATL motif used by LRP1, we tested minireceptors with mutations in each of the five potential motifs in the LRP1B tail. Only mutation of both NPXY motifs together abolished LRP1B endocytosis, suggesting that LRP1B can use either of these motifs for internalization. LRP1B contains a unique insertion of 33 amino acids not present in LRP1 that could lead to altered recognition of trafficking motifs. Surprisingly, deletion of this insertion had no effect on the endocytosis rate of LRP1B. However, replacing either half of the LRP1B tail with the corresponding LRP1 sequence markedly accelerated LRP1B endocytosis. From these data, we propose that both halves of the LRP1B cytoplasmic tail contribute to a unique global conformation, which results in less efficient recognition by endocytic adaptors and a slow endocytosis rate.
- Published
- 2007
31. E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation
- Author
-
Aaron Ciechanover, Liping Sun, Julie S. Trausch-Azar, and Alan L. Schwartz
- Subjects
Proteasome Endopeptidase Complex ,Cancer Research ,Transcription, Genetic ,Muscle Fibers, Skeletal ,Fluorescent Antibody Technique ,Biology ,Protein degradation ,MyoD ,Myoblasts ,Mice ,chemistry.chemical_compound ,MG132 ,Basic Helix-Loop-Helix Transcription Factors ,Genetics ,medicine ,Animals ,Humans ,Myocyte ,Molecular Biology ,Cell Proliferation ,Cell Nucleus ,Ubiquitin ,Myogenesis ,Helix-Loop-Helix Motifs ,Cell Differentiation ,chemistry ,Proteasome ,Biochemistry ,Proteasome inhibitor ,tissues ,C2C12 ,HeLa Cells ,medicine.drug - Abstract
The E2A proteins are basic helix-loop-helix transcription factors that regulate proliferation and differentiation in many cell types. In muscle cells, the E2A proteins form heterodimers with muscle regulatory factors such as MyoD, which then bind to DNA and regulate the transcription of target genes essential for muscle differentiation. We now demonstrate that E2A proteins are primarily localized in the nucleus in both C2C12 myoblasts and myotubes, and are degraded by the ubiquitin proteasome system evidenced by stabilization following treatment with the proteasome inhibitor, MG132. During the differentiation from myoblast to myotube, the cellular abundance of E2A proteins is relatively unaltered, despite significant changes (each approximately 5-fold) in the relative rates of protein synthesis and protein degradation via the ubiquitin-proteasome system. The rate of ubiquitin-proteasome-mediated E2A protein degradation depends on the myogenic differentiation state (t 1/2 approximately 2 h in proliferating myoblasts versus t 1/2 > 10 h in differentiated myotubes), and is also associated with cell cycle in non-muscle cells. Our findings reveal an important role for both translational and post-translational regulatory mechanisms in mediating the complex program of muscle differentiation determined by the E2A proteins.
- Published
- 2006
32. LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering β-catenin subcellular distribution
- Author
-
Yonghe Li, Alan L. Schwartz, Guojun Bu, Wenyan Lu, and Xi He
- Subjects
Cancer Research ,Beta-catenin ,Transcription, Genetic ,Mice, Nude ,Biology ,medicine.disease_cause ,Mice ,Cell Line, Tumor ,Neoplasms ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,beta Catenin ,DNA Primers ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Wnt signaling pathway ,LRP6 ,LRP5 ,Cell biology ,Cytoskeletal Proteins ,Cell Transformation, Neoplastic ,Receptors, LDL ,Low Density Lipoprotein Receptor-Related Protein-6 ,Catenin ,LDL receptor ,Trans-Activators ,biology.protein ,Cancer research ,Signal transduction ,Carcinogenesis ,Cell Division ,Subcellular Fractions - Abstract
The Wnt signaling pathway plays key roles in both embryogenesis and tumorigenesis. The low-density lipoprotein (LDL) receptor-related protein-6 (LRP6), a novel member of the expanding LDL receptor family, functions as an indispensable co-receptor for the Wnt signaling pathway. Although the role of LRP6 in embryonic development is now well established, its role in tumorigenesis is unclear. We report that LRP6 is readily expressed at the transcript level in several human cancer cell lines and human malignant tissues. Furthermore, using a retroviral gene transfer system, we find that stable expression of LRP6 in human fibrosarcoma HT1080 cells alters subcellular beta-catenin distribution such that the cytosolic beta-catenin level is significantly increased. This is accompanied by a significant increase in Wnt/beta-catenin signaling and cell proliferation. Finally, we demonstrate that LRP6 expression promotes tumorigenesis in vivo. These results thus indicate that LRP6 may function as a potential oncogenic protein by modulating Wnt/beta-catenin signaling.
- Published
- 2004
33. The Tumor Suppressor Protein p16 and the Human Papillomavirus Oncoprotein-58 E7 Are Naturally Occurring Lysine-less Proteins That Are Degraded by the Ubiquitin System
- Author
-
Alan L. Schwartz, Ifat Fajerman, Ulf Hellman, Tamar Ziv, Ronen Ben-Saadon, and Aaron Ciechanover
- Subjects
biology ,Oncogene Proteins ,Lysine ,Cell Biology ,Ubiquitin-conjugating enzyme ,medicine.disease_cause ,Biochemistry ,F-box protein ,Ubiquitin ligase ,Ubiquitin ,Papillomavirus E7 Proteins ,Protein targeting ,biology.protein ,medicine ,Molecular Biology - Abstract
Conjugation of ubiquitin to an internal lysine is the initial step in the degradation of the majority of the substrates of the ubiquitin system. For several substrates, it has been shown that the first ubiquitin moiety is conjugated to the N-terminal residue. In all these substrates, however, the internal lysines also played a role in modulating their stability. To better understand the physiological significance of this novel mode of modification, it was important to identify proteins in which degradation is completely dependent on N-terminal ubiquitination. Also, although the experimental evidence for N-terminal ubiquitination is rather strong, nevertheless, it has remained indirect. Here we demonstrate that an important group of proteins that are targeted via N-terminal ubiquitination are the naturally occurring lysine-less proteins such as the human papillomavirus (HPV)-58 E7 oncoprotein and the cell cycle inhibitor and tumor suppressor p16(INK4a). For these proteins, the only residue that can be targeted is the N-terminal residue. Interestingly, p16(INK4a) is degraded in a cell density-dependent manner. Importantly, we provide for the first time direct evidence for N-terminal ubiquitination. Analysis of tryptic digest of the ubiquitin conjugate of HPV-58 E7 revealed a fusion peptide that is composed of the C-terminal domain of ubiquitin and the N-terminal domain of E7. With the abundance of native lysine-less proteins, among which are important viral and cell regulators, this novel mode of protein targeting has implications for both physiological and pathophysiological processes.
- Published
- 2004
34. Ubiquitin-Proteasome-mediated Degradation of Id1 Is Modulated by MyoD
- Author
-
Jody M. Lingbeck, Julie S. Trausch-Azar, Aaron Ciechanover, and Alan L. Schwartz
- Subjects
Inhibitor of Differentiation Protein 1 ,Cytoplasm ,Proteasome Endopeptidase Complex ,Time Factors ,Transcription, Genetic ,Plasma protein binding ,Biology ,Transfection ,MyoD ,Biochemistry ,Protein structure ,Multienzyme Complexes ,Humans ,Molecular Biology ,Transcription factor ,MyoD Protein ,Cell Nucleus ,Alanine ,Ubiquitin ,Lysine ,DNA ,Cell Biology ,Molecular biology ,Protein Structure, Tertiary ,Cell biology ,Repressor Proteins ,Cysteine Endopeptidases ,Microscopy, Fluorescence ,Mutation ,Mutagenesis, Site-Directed ,Nuclear localization sequence ,HeLa Cells ,Plasmids ,Protein Binding ,Transcription Factors - Abstract
Degradation of many short-lived cellular proteins such as the transcription factor MyoD occurs via the ubiquitin-proteasome pathway. MyoD, similar to many rapidly degraded regulatory factors, interacts with several high affinity binding partners, including members of the Id (inhibitors of DNA binding) family. Following transfection to HeLa cells, Id1 is localized to the nucleus and rapidly (t(1/2) approximately 1 h) degraded via the ubiquitin-proteasome system. Mutagenesis of lysine residues within the putative nuclear localization region (amino acids 68-82) directs Id1(NLS) to the cytoplasm yet confers an increased rate of degradation (t(1/2) approximately 0.5 h). Id1 in which all lysine residues were mutagenized to alanine (lysineless Id1) was also rapidly degraded (t(1/2) approximately 0.6 h). Addition of a Myc(6) tag to the N terminus of lysine-less Id1 markedly stabilized Id1 (t(1/2)10 h) and suggests degradation via the N terminus-dependent pathway. Co-transfection of MyoD with Id1 or Id1(NLS) increases Id1 or Id1(NLS) within the nucleus and markedly reduces the rate of Id1 or Id1(NLS) degradation. These results thus demonstrate that in vivo MyoD modulates the rate of Id1 degradation and suggest a dynamic interplay of these factors.
- Published
- 2004
35. Determinants of Nuclear and Cytoplasmic Ubiquitin-mediated Degradation of MyoD
- Author
-
Julie S. Trausch-Azar, Jody M. Lingbeck, Aaron Ciechanover, and Alan L. Schwartz
- Subjects
Cell Nucleus ,Cytoplasm ,Ubiquitin ,Hydrolysis ,Fluorescent Antibody Technique ,Cell Biology ,Biology ,Protein degradation ,MyoD ,Biochemistry ,Cell biology ,Mutagenesis, Site-Directed ,biology.protein ,Humans ,Nuclear export signal ,Molecular Biology ,Transcription factor ,Nuclear localization sequence ,HeLa Cells ,MyoD Protein ,Myc-tag - Abstract
The ubiquitin-proteasome system is responsible for the regulation and turnover of many short-lived proteins both in the cytoplasm and in the nucleus. Degradation can occur via two distinct pathways, an N terminus-dependent pathway and a lysine-dependent pathway. The pathways are characterized by the site of initial ubiquitination of the protein, the N terminus or an internal lysine, respectively. MyoD, a basic helix-loop-helix transcription factor, is a substrate for the ubiquitin-proteasome pathway and is degraded in the nucleus. It is preferentially tagged for degradation on the N terminus and thus is degraded by the N terminus-dependent pathway. Addition of a 6x Myc tag to the N terminus of MyoD can force degradation through the lysine-dependent pathway by preventing ubiquitination at the N-terminal site. Modifications of the nuclear localization signal and nuclear export signal of MyoD restrict ubiquitination and degradation to the cytoplasm or the nucleus. Using these mutants, we determined which degradation pathway is dominant in the cytoplasm and the nucleus. Our results suggest that the lysine-dependent pathway is the more active pathway within the cytoplasm, whereas in the nucleus the two pathways are both active in protein degradation.
- Published
- 2003
36. α2-Macroglobulin Complexes with and Mediates the Endocytosis of β-Amyloid Peptide via Cell Surface Low-Density Lipoprotein Receptor-Related Protein
- Author
-
Guojun Bu, Masaaki Narita, David M. Holtzman, and Alan L. Schwartz
- Subjects
Plasma protein binding ,Biology ,Endocytosis ,Biochemistry ,Mice ,Neuroblastoma ,Cellular and Molecular Neuroscience ,Tumor Cells, Cultured ,Animals ,Humans ,alpha-Macroglobulins ,Receptors, Immunologic ,Beta (finance) ,Receptor ,Amyloid beta-Peptides ,Fibroblasts ,Ligand (biochemistry) ,Macroglobulin ,Cell biology ,Kinetics ,LDL receptor ,Chromatography, Gel ,Electrophoresis, Polyacrylamide Gel ,lipids (amino acids, peptides, and proteins) ,Low Density Lipoprotein Receptor-Related Protein-1 ,Protein Binding ,Lipoprotein - Abstract
A primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid (A beta) in the brain of afflicted individuals. However, A beta is produced continuously as a soluble protein in healthy individuals where it is detected in serum and CSF, suggesting the existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that A beta forms stable complexes with activated alpha2-macroglobulin (alpha2M*), a physiological ligand for the low-density lipoprotein receptor-related protein (LRP) that is abundantly expressed in the CNS. These alpha2M*/125I-A beta complexes are immunoreactive with both anti-A beta and anti-alpha2M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that alpha2M*/125I-A beta complexes can be degraded by glioblastoma cells and fibroblasts via LRP, because degradation is partially inhibited by receptor-associated protein (RAP), an antagonist of ligand interactions with LRP. In contrast, the degradation of free 125I-A beta is not inhibited by RAP and thus must be mediated via an LRP-independent pathway. These results suggest that LRP can function as a clearance receptor for A beta via a physiological ligand.
- Published
- 2002
37. Low Density Lipoprotein (LDL) Receptor-related Protein 1B Impairs Urokinase Receptor Regeneration on the Cell Surface and Inhibits Cell Migration
- Author
-
Alan L. Schwartz, Wenyan Lu, Jane M. Knisely, Lynn M. McCormick, Jack Henkin, Guojun Bu, Yonghe Li, and Jieyi Wang
- Subjects
Low-density lipoprotein receptor gene family ,LRP1B ,Receptors, Cell Surface ,CHO Cells ,Cell Biology ,Biology ,Endocytosis ,Urokinase-Type Plasminogen Activator ,Biochemistry ,LRP1 ,Receptors, Urokinase Plasminogen Activator ,Cell biology ,Urokinase receptor ,chemistry.chemical_compound ,Receptors, LDL ,chemistry ,Cell Movement ,Cricetinae ,Plasminogen activator inhibitor-1 ,Plasminogen Activator Inhibitor 1 ,LDL receptor ,Animals ,Molecular Biology ,Plasminogen activator ,LDL-Receptor Related Proteins - Abstract
The low density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a newly identified member of the LDL receptor family and is closely related to LRP. It was discovered as a putative tumor suppressor and is frequently inactivated in lung cancer cells. In the present study, we used an LRP1B minireceptor (mLRP1B4), which mimics the function and trafficking of LRP1B, to explore the roles of LRP1B on the plasminogen activation system. We found that mLRP1B4 and urokinase plasminogen activator receptor (uPAR) form immunoprecipitable complexes on the cell surface in the presence of complexes of uPA and its inhibitor, plasminogen activator inhibitor type-1 (PAI-1). However, compared with cells expressing the analogous LRP minireceptor (mLRP4), cells expressing mLRP1B4 display a substantially slower rate of uPA.PAI-1 complex internalization. Expression of mLRP1B4, or an mLRP4 mutant deficient in endocytosis, leads to an accumulation of uPAR at the cell surface and increased cell-associated uPA and PAI-1 when compared with cells expressing mLRP4. In addition, we found that expression of mLRP1B or the mLRP4 endocytosis mutant impairs the regeneration of unoccupied uPAR on the cell surface and that this correlates with a diminished rate of cell migration. Taken together, these results demonstrate that LRP1B can function as a negative regulator of uPAR regeneration and cell migration.
- Published
- 2002
38. Cellular Catabolism of Lipid Poor Apolipoprotein E via Cell Surface LDL Receptor-Related Protein
- Author
-
David Holtzman, Alan L. Schwartz, Anne M. Fagan, Xianlin Han, Mary Jo LaDu, Guojun Bu, Masaaki Narita, Li Yu, and Richard W. Gross
- Subjects
Apolipoprotein E ,Spectrometry, Mass, Electrospray Ionization ,In Vitro Techniques ,Lipoproteins, VLDL ,Biology ,Endocytosis ,Biochemistry ,Apolipoproteins E ,Iodine Radioisotopes ,Mice ,chemistry.chemical_compound ,Animals ,Humans ,Receptor ,Molecular Biology ,Cholesterol ,Cholesterol, HDL ,General Medicine ,Molecular biology ,chemistry ,Low-density lipoprotein ,LDL receptor ,lipids (amino acids, peptides, and proteins) ,Rabbits ,Low Density Lipoprotein Receptor-Related Protein-1 ,Lipoprotein - Abstract
Apolipoprotein E (apoE), an apoprotein involved in lipid transport in both the plasma and within the brain, mediates the binding of lipoproteins to members of the low density lipoprotein (LDL) receptor family including the LDL receptor and the LDL receptor-related protein (LRP). ApoE/LRP interactions may be particularly important in brain where both are expressed at high levels, and polymorphisms in the apoE and LRP genes have been linked to AD. To date, only apoE-enriched lipoproteins have been shown to be LRP ligands. To investigate further whether other, more lipid-poor forms of apoE interact with LRP, we tested whether lipid-free apoE in the absence of lipoprotein particles interacts with its cell-surface receptors. No detectable lipid was found associated with bacterially expressed and purified apoE either prior to or following incubation with cells when analyzed by electrospray ionization mass spectrometry. We found that the degradation of lipid-poor (125)I-apoE was significantly higher in wild type as compared to LRP-deficient cells, and was inhibited by receptor-associated protein (RAP). In contrast, (125)I-apoE-enriched beta-VLDL was degraded by both LRP and the LDL receptor. When analyzed via a single cycle of endocytosis, (125)I-apoE was internalized prior to its subsequent intracellular degradation with kinetics typical of receptor-mediated endocytosis. Thus, we conclude that a very lipid-poor form of apoE can be catabolized via cell surface LRP, suggesting that the conformation of apoE necessary for recognition by LRP can be imposed by situations other than an apoE-enriched lipoprotein.
- Published
- 2002
39. Proteasome Regulates the Delivery of LDL Receptor-related Protein into the Degradation Pathway
- Author
-
Peter van Kerkhof, Guojun Bu, Hans J. Geuze, Yonghe Li, Ger J. Strous, Lynn M. McCormick, Lora Melman, and Alan L. Schwartz
- Subjects
Proteasome Endopeptidase Complex ,Time Factors ,Leupeptins ,Immunoelectron microscopy ,Amino Acid Motifs ,Blotting, Western ,Endocytic cycle ,Lactacystin ,CHO Cells ,Cysteine Proteinase Inhibitors ,Biology ,Ligands ,Endocytosis ,Article ,chemistry.chemical_compound ,Multienzyme Complexes ,Cricetinae ,MG132 ,Tumor Cells, Cultured ,Animals ,Humans ,Microscopy, Immunoelectron ,Receptor ,Molecular Biology ,Cell Biology ,Flow Cytometry ,Precipitin Tests ,Recombinant Proteins ,Transport protein ,Cell biology ,Lipoproteins, LDL ,Cysteine Endopeptidases ,Kinetics ,Protein Transport ,Microscopy, Fluorescence ,chemistry ,LDL receptor ,lipids (amino acids, peptides, and proteins) ,Low Density Lipoprotein Receptor-Related Protein-1 ,Protein Binding - Abstract
The low-density lipoprotein receptor (LDLR)-related protein (LRP) is a multiligand endocytic receptor that has broad cellular and physiological functions. Previous studies have shown that both tyrosine-based and di-leucine motifs within the LRP cytoplasmic tail are responsible for mediating its rapid endocytosis. Little is known, however, about the mechanism by which LRP is targeted for degradation. By examining both endogenous full-length and a minireceptor form of LRP, we found that proteasomal inhibitors, MG132 and lactacystin, prolong the cellular half-life of LRP. The presence of proteasomal inhibitors also significantly increased the level of LRP at the cell surface, suggesting that the delivery of LRP to the degradation pathway was blocked at a compartment from which recycling of the receptor to the cell surface still occurred. Immunoelectron microscopy analyses demonstrated a proteasomal inhibitor-dependent reduction in LRP minireceptor within both limiting membrane and internal vesicles of the multivesicular bodies, which are compartments that lead to receptor degradation. In contrast to the growth hormone receptor, we found that the initial endocytosis of LRP minireceptor does not require a functional ubiquitin–proteasome system. Finally, using truncated cytoplasmic mutants of LRP minireceptors, we found that a region of 19 amino acids within the LRP tail is required for proteasomal regulation. Taken together our results provide strong evidence that the cellular turnover of a cargo receptor, i.e., LRP, is regulated by the proteasomal system, suggesting a broader function of the proteasome in regulating the trafficking of receptors into the degradation pathway.
- Published
- 2002
40. Ubiquitin-mediated degradation of cellular proteins in health and disease
- Author
-
Alan L. Schwartz and Aaron Ciechanover
- Subjects
chemistry.chemical_classification ,Mutation ,Hepatology ,biology ,Disease ,Metabolism ,medicine.disease_cause ,Enzyme ,medicine.anatomical_structure ,Biochemistry ,Ubiquitin ,chemistry ,Lysosome ,Proteins metabolism ,medicine ,biology.protein ,Cellular proteins - Published
- 2002
41. Isoform-specific SCF(Fbw7) ubiquitination mediates differential regulation of PGC-1α
- Author
-
Julie S, Trausch-Azar, Mona, Abed, Amir, Orian, and Alan L, Schwartz
- Subjects
Cytoplasm ,Proteasome Endopeptidase Complex ,F-Box-WD Repeat-Containing Protein 7 ,F-Box Proteins ,Ubiquitin-Protein Ligases ,Ubiquitination ,Cell Cycle Proteins ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Article ,Humans ,Protein Isoforms ,Phosphorylation ,Cells, Cultured ,Transcription Factors - Abstract
The E3 ubiquitin ligase and tumor suppressor SCF(Fbw7) exists as three isoforms that govern the degradation of a host of critical cell regulators, including c-Myc, cyclin E, and PGC-1α. Peroxisome proliferator activated receptor-gamma coactivator 1α (PGC-1α) is a transcriptional coactivator with broad effects on cellular energy metabolism. Cellular PGC-1α levels are tightly controlled in a dynamic state by the balance of synthesis and rapid degradation via the ubiquitin-proteasome system. Isoform-specific functions of SCF(Fbw7) are yet to be determined. Here, we show that the E3 ubiquitin ligase, SCF(Fbw7), regulates cellular PGC-1α levels via two independent, isoform-specific, mechanisms. The cytoplasmic isoform (SCF(Fbw7β)) reduces cellular PGC-1α levels via accelerated ubiquitin-proteasome degradation. In contrast, the nuclear isoform (SCF(Fbw7α)) increases cellular PGC-1α levels and protein stability via inhibition of ubiquitin-proteasomal degradation. When nuclear Fbw7α proteins are redirected to the cytoplasm, cellular PGC-1α protein levels are reduced through accelerated ubiquitin-proteasomal degradation. We find that SCF(Fbw7β) catalyzes high molecular weight PGC-1α-ubiquitin conjugation, whereas SCF(Fbw7α) produces low molecular weight PGC-1α-ubiquitin conjugates that are not effective degradation signals. Thus, selective ubiquitination by specific Fbw7 isoforms represents a novel mechanism that tightly regulates cellular PGC-1α levels. Fbw7 isoforms mediate degradation of a host of regulatory proteins. The E3 ubiquitin ligase, Fbw7, mediates PGC-1α levels via selective isoform-specific ubiquitination. Fbw7β reduces cellular PGC-1α via ubiquitin-mediated degradation, whereas Fbw7α increases cellular PGC-1α via ubiquitin-mediated stabilization.
- Published
- 2014
42. The Nuclear Ubiquitin-Proteasome System Degrades MyoD
- Author
-
Aaron Ciechanover, Julie S. Trausch-Azar, Alan L. Schwartz, Z. Elizabeth Floyd, and Eyal Reinstein
- Subjects
Proteasome Endopeptidase Complex ,Biology ,MyoD ,Biochemistry ,HeLa ,Adenosine Triphosphate ,Multienzyme Complexes ,medicine ,Humans ,Nuclear protein ,Nuclear export signal ,Ubiquitins ,Molecular Biology ,MyoD Protein ,Cell Nucleus ,Nucleoplasm ,Hydrolysis ,Cell Biology ,biology.organism_classification ,In vitro ,Cell biology ,Cysteine Endopeptidases ,medicine.anatomical_structure ,Proteasome ,Fatty Acids, Unsaturated ,Nucleus ,HeLa Cells - Abstract
Many short-lived nuclear proteins are targeted for degradation by the ubiquitin-proteasome pathway. The role of the nucleus in regulating the turnover of these proteins is not well defined, although many components of the ubiquitin-proteasome system are localized in the nucleus. We have used nucleoplasm from highly purified HeLa nuclei to examine the degradation of a physiological substrate of the ubiquitin-proteasome system (MyoD). In vitro studies using inhibitors of the system demonstrate MyoD is degraded via the ubiquitin-proteasome pathway in HeLa nucleoplasm. Purified nucleoplasm in vitro also supports the generation of high molecular mass MyoD-ubiquitin adducts. In addition, in vivo studies, using leptomycin B to inhibit nuclear export, demonstrate that MyoD is degraded in HeLa cells by the nuclear ubiquitin-proteasome system.
- Published
- 2001
43. Video Review
- Author
-
Alan L. Schwartz
- Subjects
Clinical Psychology - Published
- 2001
44. Harmonic analysis on compact commutative hypergroups: The role of the maximum subgroup
- Author
-
Alan L. Schwartz and Oliver Gebuhrer
- Subjects
Algebra ,Harmonic analysis ,Pure mathematics ,Development (topology) ,General Mathematics ,Banach algebra ,Mathematical proof ,Commutative property ,Measure (mathematics) ,Analysis ,Axiom ,Haar measure ,Mathematics - Abstract
The article is written in two parts: Part I develops basic results within a new axiomatic development introduced by one of the authors in a previous work. It allows for a larger category of measure algebras to be included than did the former axioms (DJS-hypergroups). While new and independent proofs are given, this part of the article is expository.
- Published
- 2000
45. Recombinant full-length tissue factor pathway inhibitor fails to bind to the cell surface: implications for catabolism in vitro and in vivo
- Author
-
Alan L. Schwartz, Guyu Ho, George J. Broze, and Masaaki Narita
- Subjects
Catalytic complex ,Immunology ,Cell Biology ,Hematology ,Plasma protein binding ,Biology ,Biochemistry ,Protease inhibitor (biology) ,Tissue factor ,Tissue factor pathway inhibitor ,Coagulation ,In vivo ,medicine ,Receptor ,medicine.drug - Abstract
Tissue factor pathway inhibitor (TFPI) plays a key role in the regulation of tissue factor-initiated blood coagulation secondary to loss of the integrity of the blood vessel wall. TFPI is a naturally occurring Kunitz-type protease inhibitor that inhibits coagulation factor Xa and, in a factor Xa-dependent manner, mediates feedback inhibition of the factor VIIa/tissuefactor catalytic complex. In vivo full-length TFPI is thought to be primarily bound to the vascular endothelium and the high affinity binding requires an intact carboxy terminus. Here we describe a full-length TFPI molecule, expressed in mouse C127 cells (TFPIC127), which exhibits virtually no cellular binding yet contains the intact carboxy terminus. This TFPI (TFPIC127) is neither internalized nor degraded via the TFPI endocytic receptor, LDL-receptor–related protein. Pharmacokinetic studies of TFPIC127 in vivo demonstrate a 10-fold prolongation in the plasma half-life, compared with that of bacterial recombinant TFPI.
- Published
- 2000
46. Measure algebras associated with orthogonal polynomials
- Author
-
William C. Connett and Alan L. Schwartz
- Published
- 2000
47. Structural Motifs Involved in Ubiquitin-Mediated Processing of the NF-κB Precursor p105: Roles of the Glycine-Rich Region and a Downstream Ubiquitination Domain
- Author
-
Aaron Ciechanover, Chaim Kahana, Alan L. Schwartz, Simon T. Whiteside, Amir Orian, and Alain Israël
- Subjects
Proteasome Endopeptidase Complex ,Protein subunit ,Molecular Sequence Data ,Transfection ,DNA-binding protein ,Ubiquitin ,Animals ,Humans ,Amino Acid Sequence ,Protein Precursors ,Structural motif ,Cell Growth and Development ,Ubiquitins ,Molecular Biology ,Peptide sequence ,Sequence Deletion ,biology ,NF-kappa B ,Cell Biology ,Ubiquitin ligase ,DNA-Binding Proteins ,Biochemistry ,Proteasome ,COS Cells ,Mutation ,biology.protein ,Protein Processing, Post-Translational ,HeLa Cells ,Peptide Hydrolases - Abstract
The ubiquitin proteolytic system plays a major role in a variety of basic cellular processes. In the majority of these processes, the target proteins are completely degraded. In one exceptional case, generation of the p50 subunit of the transcriptional regulator NF-kappaB, the precursor protein p105 is processed in a limited manner: the N-terminal domain yields the p50 subunit, whereas the C-terminal domain is degraded. The identity of the mechanisms involved in this unique process have remained elusive. It has been shown that a Gly-rich region (GRR) at the C-terminal domain of p50 is an important processing signal. Here we show that the GRR does not interfere with conjugation of ubiquitin to p105 but probably does interfere with the processing of the ubiquitin-tagged precursor by the 26S proteasome. Structural analysis reveals that a short sequence containing a few Gly residues and a single essential Ala is sufficient to generate p50. Mechanistically, the presence of the GRR appears to stop further degradation of p50 and to stabilize the molecule. It appears that the localization of the GRR within p105 plays an important role in directing processing: transfer of the GRR within p105 or insertion of the GRR into homologous or heterologous proteins is not sufficient to promote processing in most cases, which is probably due to the requirement for an additional specific ubiquitination and/or recognition domain(s). Indeed, we have shown that amino acid residues 441 to 454 are important for processing. In particular, both Lys 441 and Lys 442 appear to serve as major ubiquitination targets, while residues 446 to 454 are independently important for processing and may serve as the ubiquitin ligase recognition motif.
- Published
- 1999
48. The Ubiquitin-Proteasome Pathway and Pathogenesis of Human Diseases
- Author
-
Aaron Ciechanover and Alan L. Schwartz
- Subjects
Proteasome Endopeptidase Complex ,Viral pathogenesis ,Antigen presentation ,Receptors, Cell Surface ,Protein degradation ,Ion Channels ,General Biochemistry, Genetics and Molecular Biology ,Cell Physiological Phenomena ,Pathogenesis ,Muscular Diseases ,Ubiquitin ,Neoplasms ,Humans ,Disease ,Receptor ,Ubiquitins ,Antigen Presentation ,biology ,Wasting Syndrome ,Cell Cycle ,Genetic Diseases, Inborn ,Proteins ,General Medicine ,Cell cycle ,Cell biology ,Immune System Diseases ,Biochemistry ,Proteasome ,Virus Diseases ,biology.protein ,Peptide Hydrolases - Abstract
The ubiquitin-proteasome pathway plays a pivotal role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway involves an enzymatic cascade through which multiple ubiquitin molecules are covalently attached to the protein substrate, which is then degraded by the 26S proteasome complex. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndroome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. The molecular mechanisms that underlie these processes are being unraveled at present.
- Published
- 1999
49. Product formulas and convolutions for the radial oblate spheroidal wave functions
- Author
-
Alan L. Schwartz, William C. Connett, and Clemens Markett
- Subjects
Helmholtz equation ,Differential equation ,Homogeneous differential equation ,Product (mathematics) ,Mathematical analysis ,Separation of variables ,First-order partial differential equation ,Wave function ,Wave equation ,Mathematics - Published
- 1999
50. RAP, a novel type of ER chaperone
- Author
-
Guojun Bu and Alan L. Schwartz
- Subjects
LRP1B ,Biology ,Endoplasmic Reticulum ,medicine.disease_cause ,LDL-receptor-related protein-associated protein ,Protein targeting ,medicine ,Humans ,Gene family ,LDL-Receptor Related Protein-Associated Protein ,Secretory pathway ,Glycoproteins ,Endoplasmic reticulum ,fungi ,Cell Biology ,Transport protein ,Cell biology ,body regions ,Eukaryotic Cells ,Receptors, LDL ,Biochemistry ,CDC37 ,biology.protein ,sense organs ,Carrier Proteins ,Molecular Chaperones - Abstract
Members of the low-density lipoprotein (LDL) receptor gene family play an important role in cellular uptake of various extracellular ligands. Recent studies have shown that a 39-kDa protein known as RAP (receptor-associated protein) serves as a molecular chaperone to assist the folding of certain LDL-receptor family proteins and their passage through the secretory pathway. In this review, the authors discuss our current understanding of the roles of RAP as a molecular chaperone/escort protein and present a model of how RAP might carry out these functions.
- Published
- 1998
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