Emerging Roles of P53 Family Members in Glucose Metabolism
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Supplement 1 Overview of Dystonia Genes
Supplement 1 Overview of genes that may cause dystonia in children and adolescents Gene (OMIM) Disease name/phenotype Mode of inheritance 1: (Formerly called) Primary dystonias (DYTs): TOR1A (605204) DYT1: Early-onset generalized AD primary torsion dystonia (PTD) TUBB4A (602662) DYT4: Whispering dystonia AD GCH1 (600225) DYT5: GTP-cyclohydrolase 1 AD deficiency THAP1 (609520) DYT6: Adolescent onset torsion AD dystonia, mixed type PNKD/MR1 (609023) DYT8: Paroxysmal non- AD kinesigenic dyskinesia SLC2A1 (138140) DYT9/18: Paroxysmal choreoathetosis with episodic AD ataxia and spasticity/GLUT1 deficiency syndrome-1 PRRT2 (614386) DYT10: Paroxysmal kinesigenic AD dyskinesia SGCE (604149) DYT11: Myoclonus-dystonia AD ATP1A3 (182350) DYT12: Rapid-onset dystonia AD parkinsonism PRKRA (603424) DYT16: Young-onset dystonia AR parkinsonism ANO3 (610110) DYT24: Primary focal dystonia AD GNAL (139312) DYT25: Primary torsion dystonia AD 2: Inborn errors of metabolism: GCDH (608801) Glutaric aciduria type 1 AR PCCA (232000) Propionic aciduria AR PCCB (232050) Propionic aciduria AR MUT (609058) Methylmalonic aciduria AR MMAA (607481) Cobalamin A deficiency AR MMAB (607568) Cobalamin B deficiency AR MMACHC (609831) Cobalamin C deficiency AR C2orf25 (611935) Cobalamin D deficiency AR MTRR (602568) Cobalamin E deficiency AR LMBRD1 (612625) Cobalamin F deficiency AR MTR (156570) Cobalamin G deficiency AR CBS (613381) Homocysteinuria AR PCBD (126090) Hyperphelaninemia variant D AR TH (191290) Tyrosine hydroxylase deficiency AR SPR (182125) Sepiaterine reductase -
1 Silencing Branched-Chain Ketoacid Dehydrogenase Or
bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling Running title: BCKAs impair insulin signaling Dipsikha Biswas1, PhD, Khoi T. Dao1, BSc, Angella Mercer1, BSc, Andrew Cowie1 , BSc, Luke Duffley1, BSc, Yassine El Hiani2, PhD, Petra C. Kienesberger1, PhD, Thomas Pulinilkunnil1†, PhD 1Department of Biochemistry and Molecular Biology, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada, 2Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. †Correspondence to Thomas Pulinilkunnil, PhD Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John E2L4L5, New Brunswick, Canada. Telephone: (506) 636-6973; Fax: (506) 636-6001; email: [email protected]. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International -
Transglutaminase-Catalyzed Inactivation Of
Proc. Natl. Acad. Sci. USA Vol. 94, pp. 12604–12609, November 1997 Medical Sciences Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and a-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length ARTHUR J. L. COOPER*†‡§, K.-F. REX SHEU†‡,JAMES R. BURKE¶i,OSAMU ONODERA¶i, WARREN J. STRITTMATTER¶i,**, ALLEN D. ROSES¶i,**, AND JOHN P. BLASS†‡,†† Departments of *Biochemistry, †Neurology and Neuroscience, and ††Medicine, Cornell University Medical College, New York, NY 10021; ‡Burke Medical Research Institute, Cornell University Medical College, White Plains, NY 10605; and Departments of ¶Medicine, **Neurobiology, and iDeane Laboratory, Duke University Medical Center, Durham, NC 27710 Edited by Louis Sokoloff, National Institutes of Health, Bethesda, MD, and approved August 28, 1997 (received for review April 24, 1997) ABSTRACT Several adult-onset neurodegenerative dis- Q12-containing peptide (16). In the work of Kahlem et al. (16) the eases are caused by genes with expanded CAG triplet repeats largest Qn domain studied was Q18. We found that both a within their coding regions and extended polyglutamine (Qn) nonpathological-length Qn domain (n 5 10) and a longer, patho- domains within the expressed proteins. Generally, in clinically logical-length Qn domain (n 5 62) are excellent substrates of affected individuals n > 40. Glyceraldehyde 3-phosphate dehy- tTGase (17, 18). drogenase binds tightly to four Qn disease proteins, but the Burke et al. (1) showed that huntingtin, huntingtin-derived significance of this interaction is unknown. We now report that fragments, and the dentatorubralpallidoluysian atrophy protein purified glyceraldehyde 3-phosphate dehydrogenase is inacti- bind selectively to glyceraldehyde 3-phosphate dehydrogenase vated by tissue transglutaminase in the presence of glutathione (GAPDH) in human brain homogenates and to immobilized S-transferase constructs containing a Qn domain of pathological rabbit muscle GAPDH. -
Oncorequisite Role of an Aldehyde Dehydrogenase in the Pathogenesis of T-Cell Acute Lymphoblastic Leukemia
Acute Lymphoblastic Leukemia SUPPLEMENTARY APPENDIX Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia Chujing Zhang, 1 Stella Amanda, 1 Cheng Wang, 2 Tze King Tan, 1 Muhammad Zulfaqar Ali, 1 Wei Zhong Leong, 1 Ley Moy Ng, 1 Shojiro Kitajima, 3 Zhenhua Li, 4 Allen Eng Juh Yeoh, 1,4 Shi Hao Tan 1 and Takaomi Sanda 1,5 1Cancer Science Institute of Singapore, National University of Singapore, Singapore; 2Department of Anatomy, National University of Singapore, Singapore; 3Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan; 4VIVA-NUS CenTRAL, Department of Pedi - atrics, National University of Singapore, Singapore and 5Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ©2021 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2019.245639 Received: December 18, 2019. Accepted: May 14, 2020. Pre-published: May 15, 2020. Correspondence: TAKAOMI SANDA - [email protected] Zhang et al Roles of ALDH in T-ALL Supplementary Information Supplementary Materials and Methods Cell culture and reagents All human leukemia cell lines were cultured in RPMI-1640 medium (BioWest) supplemented with 10% FBS (BioWest). 293T cells were maintained in DMEM medium (BioWest) supplemented with 10% FBS and penicillin/streptomycin (Life Technologies). All-trans retinaldehyde was purchased from Sigma-Aldrich. Glucose free and Glutamine free RPMI- 1640 media were purchased from ThermoFisher. Patient derived xenograft (PDX) sample T-ALL patient-derived PDX sample (DFCI15) was kindly provided by Alejandro Gutierrez (Boston Children’s Hospital, Boston). Mouse studies were conducted according to the recommendations from the Institutional Animal Care and Use Committee (IACUC) and all protocols were approved by the Committee at the National University of Singapore (NUS). -
1 Silencing Branched-Chain Ketoacid Dehydrogenase Or
bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling Running title: BCKAs impair insulin signaling Dipsikha Biswas1, PhD, Khoi T. Dao1, BSc, Angella Mercer1, BSc, Andrew Cowie1 , BSc, Luke Duffley1, BSc, Yassine El Hiani2, PhD, Petra C. Kienesberger1, PhD, Thomas Pulinilkunnil1†, PhD 1Department of Biochemistry and Molecular Biology, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada, 2Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada. †Correspondence to Thomas Pulinilkunnil, PhD Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John E2L4L5, New Brunswick, Canada. Telephone: (506) 636-6973; Fax: (506) 636-6001; email: [email protected]. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.960153; this version posted February 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International -
Aerobic Glycolysis Fuels Platelet Activation: Small-Molecule Modulators of Platelet Metabolism As Anti-Thrombotic Agents
ARTICLE Platelet Biology & its Disorders Aerobic glycolysis fuels platelet activation: Ferrata Storti Foundation small-molecule modulators of platelet metabolism as anti-thrombotic agents Paresh P. Kulkarni,1† Arundhati Tiwari,1† Nitesh Singh,1 Deepa Gautam,1 Vijay K. Sonkar,1 Vikas Agarwal2 and Debabrata Dash1 1Department of Biochemistry, Institute of Medical Sciences and 2Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Haematologica 2019 Pradesh, India Volume 104(4):806-818 † PPK and AT contributed equally to this work. ABSTRACT latelets are critical to arterial thrombosis, which underlies myocardial infarction and stroke. Activated platelets, regardless of the nature of Ptheir stimulus, initiate energy-intensive processesthat sustain throm- bus, while adapting to potential adversities of hypoxia and nutrient depri- vation within the densely packed thrombotic milieu. We report here that stimulated platelets switch their energy metabolism to robicae glycolysis by modulating enzymes at key checkpoints in glucose metabolism. We found that aerobic glycolysis, in turn, accelerates flux through the pentose phos- phate pathway and supports platelet activation. Hence, reversing metabolic adaptations of platelets could be an effective alternative to conventional anti-platelet approaches, which are crippled by remarkable redundancy in platelet agonists and ensuing signaling pathways. In support of this hypoth- esis, small-molecule modulators of pyruvate dehydrogenase, pyruvate kinase M2 and glucose-6-phosphate dehydrogenase, all of which impede aerobic glycolysis and/or the pentose phosphate pathway, restrained the Correspondence: agonist-induced platelet responsesex vivo. These drugs, which include the DEBABRATA DASH anti-neoplastic candidate, dichloroacetate, and the Food and Drug [email protected] Administration-approved dehydroepiandrosterone, profoundly impaired thrombosis in mice, thereby exhibiting potential as anti-thrombotic agents. -
6-Phosphofructo-2-Kinase/Fructose-2
Published OnlineFirst August 7, 2019; DOI: 10.1158/1078-0432.CCR-18-3448 Translational Cancer Mechanisms and Therapy Clinical Cancer Research 6-Phosphofructo-2-Kinase/Fructose-2,6- Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers Hailing Yang1, Zhang Shu1,2,Yongying Jiang3, Weiqun Mao1, Lan Pang1, Abena Redwood4, Sabrina L. Jeter-Jones4, Nicholas B. Jennings5, Argentina Ornelas6, Jinhua Zhou1, Cristian Rodriguez-Aguayo1,7, Geoffrey Bartholomeusz1, LaKesla R. Iles1, Niki M. Zacharias8, Steven W. Millward6, Gabriel Lopez-Berestein1,7, Xiao-Feng Le1, Ahmed A. Ahmed9,10, Helen Piwnica-Worms4, Anil K. Sood5,7, Robert C. Bast1, and Zhen Lu1 Abstract Purpose: Paclitaxel is an integral component of primary Results: Knockdown of PFKFB2 inhibited clonogenic therapy for breast and epithelial ovarian cancers, but less than growth and enhanced paclitaxel sensitivity in ovarian and half of these cancers respond to the drug. Enhancing the breast cancer cell lines with wild-type TP53 (wtTP53). response to primary therapy with paclitaxel could improve Silencing PFKFB2 significantly inhibited tumor growth and outcomes for women with both diseases. enhanced paclitaxel sensitivity in four xenografts derived Experimental Design: Twelve kinases that regulate from two ovarian and two breast cancer cell lines, and metabolism were depleted in multiple ovarian and breast prolonged survival in a triple-negative breast cancer PDX. cancer cell lines to determine whether they regulate sensi- Transfection of siPFKFB2 increased the glycolysis rate, but tivity to paclitaxel in Sulforhodamine B assays. The effects decreased the flow of intermediates through the pentose– of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase phosphate pathway in cancer cells with wtTP53,decreasing 2(PFKFB2) depletion on cell metabolomics, extracellular NADPH. -
Identification and Validation of a Six-Gene Signature Associated With
Cai et al. BMC Cancer (2020) 20:1133 https://doi.org/10.1186/s12885-020-07598-3 RESEARCH ARTICLE Open Access Identification and validation of a six-gene signature associated with glycolysis to predict the prognosis of patients with cervical cancer Luya Cai1†, Chuan Hu2†, Shanshan Yu3, Lixiao Liu1, Xiaobo Yu1, Jiahua Chen1, Xuan Liu1, Fan Lin4, Cheng Zhang4, Wenfeng Li3 and Xiaojian Yan1* Abstract Background: Cervical cancer (CC) is one of the most common gynaecological cancers. The gene signature is believed to be reliable for predicting cancer patient survival. However, there is no relevant study on the relationship between the glycolysis-related gene (GRG) signature and overall survival (OS) of patients with CC. Methods: We extracted the mRNA expression profiles of 306 tumour and 13 normal tissues from the University of California Santa Cruz (UCSC) Database. Then, we screened out differentially expressed glycolysis-related genes (DEGRGs) among these mRNAs. All patients were randomly divided into training cohort and validation cohort according to the ratio of 7: 3. Next, univariate and multivariate Cox regression analyses were carried out to select the GRG with predictive ability for the prognosis of the training cohort. Additionally, risk score model was constructed and validated it in the validation cohort. Results: Six mRNAs were obtained that were associated with patient survival. The filtered mRNAs were classified into the protective type (GOT1) and the risk type (HSPA5, ANGPTL4, PFKM, IER3 and PFKFB4). Additionally, by constructing the prognostic risk score model, we found that the OS of the high-risk group was notably poorer, which showed good predictive ability both in training cohort and validation cohort. -
Glycolysis Citric Acid Cycle Oxidative Phosphorylation Calvin Cycle Light
Stage 3: RuBP regeneration Glycolysis Ribulose 5- Light-Dependent Reaction (Cytosol) phosphate 3 ATP + C6H12O6 + 2 NAD + 2 ADP + 2 Pi 3 ADP + 3 Pi + + 1 GA3P 6 NADP + H Pi NADPH + ADP + Pi ATP 2 C3H4O3 + 2 NADH + 2 H + 2 ATP + 2 H2O 3 CO2 Stage 1: ATP investment ½ glucose + + Glucose 2 H2O 4H + O2 2H Ferredoxin ATP Glyceraldehyde 3- Ribulose 1,5- Light Light Fx iron-sulfur Sakai-Kawada, F Hexokinase phosphate bisphosphate - 4e + center 2016 ADP Calvin Cycle 2H Stroma Mn-Ca cluster + 6 NADP + Light-Independent Reaction Phylloquinone Glucose 6-phosphate + 6 H + 6 Pi Thylakoid Tyr (Stroma) z Fe-S Cyt f Stage 1: carbon membrane Phosphoglucose 6 NADPH P680 P680* PQH fixation 2 Plastocyanin P700 P700* D-(+)-Glucose isomerase Cyt b6 1,3- Pheophytin PQA PQB Fructose 6-phosphate Bisphosphoglycerate ATP Lumen Phosphofructokinase-1 3-Phosphoglycerate ADP Photosystem II P680 2H+ Photosystem I P700 Stage 2: 3-PGA Photosynthesis Fructose 1,6-bisphosphate reduction 2H+ 6 ADP 6 ATP 6 CO2 + 6 H2O C6H12O6 + 6 O2 H+ + 6 Pi Cytochrome b6f Aldolase Plastoquinol-plastocyanin ATP synthase NADH reductase Triose phosphate + + + CO2 + H NAD + CoA-SH isomerase α-Ketoglutarate + Stage 2: 6-carbonTwo 3- NAD+ NADH + H + CO2 Glyceraldehyde 3-phosphate Dihydroxyacetone phosphate carbons Isocitrate α-Ketoglutarate dehydogenase dehydrogenase Glyceraldehyde + Pi + NAD Isocitrate complex 3-phosphate Succinyl CoA Oxidative Phosphorylation dehydrogenase NADH + H+ Electron Transport Chain GDP + Pi 1,3-Bisphosphoglycerate H+ Succinyl CoA GTP + CoA-SH Aconitase synthetase -
Glycolytic Reliance Promotes Anabolism in Photoreceptors
bioRxiv preprint doi: https://doi.org/10.1101/101964; this version posted January 21, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Glycolytic reliance promotes anabolism in photoreceptors Yashodhan Chinchore, Tedi Begaj, David Wu, Eugene Drokhlyansky, Constance L. Cepko* *Departments of Genetics and Ophthalmology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [email protected] bioRxiv preprint doi: https://doi.org/10.1101/101964; this version posted January 21, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Sensory neurons capture information from the environment and convert it 2 into signals that can greatly impact the survival of an organism. These systems 3 are thus under heavy selective pressure, including for the most efficient use of 4 energy to support their sensitivity and efficiency1. In this regard, the 5 vertebrate photoreceptor cells face a dual challenge. They not only need to 6 preserve their membrane excitability via ion pumps by ATP hydrolysis2 but 7 also maintain a highly membrane rich organelle, the outer segment, which is 8 the primary site of phototransduction, creating a considerable biosynthetic 9 demand. How photoreceptors manage carbon allocation to balance their 10 catabolic and anabolic demands is poorly understood. One metabolic feature 11 of the retina is its ability to convert the majority of its glucose into lactate3,4 12 even in the presence of oxygen. -
High Expression of Metabolic Enzyme PFKFB4 Is Associated with Poor
Yao et al. Cancer Cell Int (2019) 19:165 https://doi.org/10.1186/s12935-019-0882-2 Cancer Cell International PRIMARY RESEARCH Open Access High expression of metabolic enzyme PFKFB4 is associated with poor prognosis of operable breast cancer Ling Yao1,2,3†, Lei Wang1,2,3†, Zhi‑Gang Cao1,2,3, Xin Hu1,2,3* and Zhi‑Ming Shao1,2,3,4* Abstract Background: Enhanced glycolysis in tumors, known as the Warburg efect, provides the metabolic basis of enhanced cancer cell proliferation and metastasis. The Warburg pathway enzyme 6‑phosphofructo‑2‑kinase/fructose‑ 2,6‑bisphosphatase 4 (PFKFB4) is a newly identifed key kinase that regulates transcriptional reprogramming and cell proliferation. Here we show the prognostic value of PFKFB4 expression in patients with operable breast cancer. Methods: PFKFB4 expression was evaluated by immunohistochemistry in surgical specimens retrospectively col‑ lected from 200 patients with histologically proven invasive ductal breast cancer. Kaplan–Meier survival analysis and Cox regression analysis were performed to assess the prognostic signifcance of PFKFB4 expression. Results: Kaplan–Meier survival analysis revealed that breast cancer patients with high PFKFB4 expression demon‑ strated unfavorable disease‑free survival (p 0.008) and overall survival (p 0.002). PFKFB4 had an hazard ratio (HR) of 7.38 (95% CI 1.69–32.3; p 0.008) in univariate= Cox analysis and retained prognostic= power (HR 7.44, 95% CI 1.67–33.2; p 0.009) when adjusted= by tumor size, lymph node status, grade, estrogen receptor status, human epidermal growth= factor receptor 2 status and subtype, which indicated PFKFB4 was an independent prognostic factor in breast cancer. -
Lipoyl Moieties in the Pyruvate and A-Ketoglutarate Dehydrogenase
Vol. 74, No. 10, pp 42&S-4227, October 1977 Biochemistry Acyl group and electron pair relay system: A network of interacting lipoyl moieties in the pyruvate and a-ketoglutarate dehydrogenase complexes from Escherichia coli (multienzyme complexes/thiol-disulfide interchange/crosslinking of subunits) JIMMY H. COLLINS AND LESTER J. REED Clayton Foundation Biochemical Institute and Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712 Contributed by Lester J. Reed, August 18, 1977 ABSTRACT The dihydrolipoyl transacetylase component complex by [2-'4C]pyruvate (6) and of the pyruvate-dependent of the Escherichia coli pyruvate dehydrogenase complex [pyr- reaction of N-ethyl[2,3-14C]maleimide with the complex (7) uvate:lipoate oxidoreductase (decarboxylating and acceptor- indicate the presence of two functionally active lipoyl acetylating), EC 1.2.4.11 bears two sites on each of its 24poly- moieties peptide chains that undergo reductive acetylation by on each transacetylase chain. 2-4C pyruvate and thiamin pyrophosphate, acetylation by In this communication, we confirm and extend this latter [lMClacetyl-CoA in the presence of DPNH, and reaction with finding, and we present evidence indicating that the trans- N-ethyl[2,3-14Clmaleimide in the presence of pyruvate and succinylase component of the a-ketoglutarate dehydrogenase thiamin pyrophosphate. The data strongly ir tat these sites complex bears one functionally active lipoyl moiety per chain are covalent y bound lipoyl moieties. The results of similar ex- and that the 48 lipoyl moieties in periments with the E. coli a-ketoglutarate dehydrogenase the transacetylase and the 24 complex [2-oxoglutaratelipoate oxidoreductase (decarboxylating lipoyl moieties in the transsuccinylase comprise a network that and acceptor-succinylating), EC 1±2.4.2] indicate that its dihy- functions as an acyl group and electron pair relay system drolipoyl transsuccinylase component bears only one lipoyl through thiol-disulfide and acyl-transfer reactions among all moiety on each of its 24 chains.