-
Články
- Časopisy
- Kurzy
- Témy
- Kongresy
- Videa
- Podcasty
Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2
Maintaining a balanced level of stress (protein folding, reactive oxygen radicals) is important for keeping cellular homeostasis (the ability of a cell to maintain internal equilibrium by adjusting its physiological processes). The accumulation of stress (external or internal) will trigger a well-orchestrated machinery that attempts to restore homeostasis, namely, the unfolded protein response (UPR). The UPR either restores balance to the cells or induces a cell death program, which clears the damaged cell. How this machinery activates cell survival versus cell death is not entirely clear. Here we identify a new layer in the regulation of the UPR, which determines the magnitude of this response. We demonstrate the importance of this newly identified regulatory component for cell death commitments, in response to the more severe conditions (ischemia, lack of oxygen and nutrients). Our findings highlight an undisclosed mechanism that is important for the cell death decision following severe stress conditions, while pointing to the ability to fine tune cellular response to stress.
Vyšlo v časopise: Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004348
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004348Souhrn
Maintaining a balanced level of stress (protein folding, reactive oxygen radicals) is important for keeping cellular homeostasis (the ability of a cell to maintain internal equilibrium by adjusting its physiological processes). The accumulation of stress (external or internal) will trigger a well-orchestrated machinery that attempts to restore homeostasis, namely, the unfolded protein response (UPR). The UPR either restores balance to the cells or induces a cell death program, which clears the damaged cell. How this machinery activates cell survival versus cell death is not entirely clear. Here we identify a new layer in the regulation of the UPR, which determines the magnitude of this response. We demonstrate the importance of this newly identified regulatory component for cell death commitments, in response to the more severe conditions (ischemia, lack of oxygen and nutrients). Our findings highlight an undisclosed mechanism that is important for the cell death decision following severe stress conditions, while pointing to the ability to fine tune cellular response to stress.
Zdroje
1. RonD, WalterP (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8 : 519–529.
2. SchroderM, KaufmanRJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74 : 739–789.
3. HetzC (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13 : 89–102.
4. WalterP, RonD (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334 : 1081–1086.
5. KaufmanRJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13 : 1211–1233.
6. ZhangK, KaufmanRJ (2006) The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66: S102–109.
7. WangS, KaufmanRJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197 : 857–867.
8. HazeK, YoshidaH, YanagiH, YuraT, MoriK (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10 : 3787–3799.
9. WuJ, RutkowskiDT, DuboisM, SwathirajanJ, SaundersT, et al. (2007) ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 13 : 351–364.
10. LeeK, TirasophonW, ShenX, MichalakM, PrywesR, et al. (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16 : 452–466.
11. YoshidaH, MatsuiT, YamamotoA, OkadaT, MoriK (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107 : 881–891.
12. HardingHP, ZhangY, BertolottiA, ZengH, RonD (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5 : 897–904.
13. ScheunerD, SongB, McEwenE, LiuC, LaybuttR, et al. (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Molecular cell 7 : 1165–1176.
14. HardingHP, ZhangY, ZengH, NovoaI, LuPD, et al. (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11 : 619–633.
15. LuPD, HardingHP, RonD (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 167 : 27–33.
16. MarciniakSJ, YunCY, OyadomariS, NovoaI, ZhangY, et al. (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes & development 18 : 3066–3077.
17. TabasI, RonD (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13 : 184–190.
18. YeJ, KumanovaM, HartLS, SloaneK, ZhangH, et al. (2010) The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J 29 : 2082–2096.
19. HanJ, BackSH, HurJ, LinYH, GildersleeveR, et al. (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15 : 481–490.
20. LiJ, LeeB, LeeAS (2006) Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem 281 : 7260–7270.
21. GhoshAP, KlockeBJ, BallestasME, RothKA (2012) CHOP potentially co-operates with FOXO3a in neuronal cells to regulate PUMA and BIM expression in response to ER stress. PLoS One 7: e39586.
22. HuG, ChungYL, GloverT, ValentineV, LookAT, et al. (1997) Characterization of human homologs of the Drosophila seven in absentia (sina) gene. Genomics 46 : 103–111.
23. HouseCM, MollerA, BowtellDD (2009) Siah proteins: novel drug targets in the Ras and hypoxia pathways. Cancer Res 69 : 8835–8838.
24. NakayamaK, QiJ, RonaiZ (2009) The ubiquitin ligase Siah2 and the hypoxia response. Mol Cancer Res 7 : 443–451.
25. QiJ, KimH, ScortegagnaM, RonaiZA (2013) Regulators and Effectors of Siah Ubiquitin Ligases. Cell Biochem Biophys 67 : 15–24.
26. NadeauRJ, ToherJL, YangX, KovalenkoD, FrieselR (2007) Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. J Cell Biochem 100 : 151–160.
27. QiJ, NakayamaK, GaitondeS, GoydosJS, KrajewskiS, et al. (2008) The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways. Proc Natl Acad Sci U S A 105 : 16713–16718.
28. KimH, ScimiaMC, WilkinsonD, TrellesRD, WoodMR, et al. (2011) Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia. Mol Cell 44 : 532–544.
29. CalzadoMA, de la VegaL, MollerA, BowtellDD, SchmitzML (2009) An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol 11 : 85–91.
30. FukubaH, TakahashiT, JinHG, KohriyamaT, MatsumotoM (2008) Abundance of aspargynyl-hydroxylase FIH is regulated by Siah-1 under normoxic conditions. Neurosci Lett 433 : 209–214.
31. SchofieldCJ, RatcliffePJ (2005) Signalling hypoxia by HIF hydroxylases. Biochem Biophys Res Commun 338 : 617–626.
32. WebbJD, ColemanML, PughCW (2009) Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell Mol Life Sci 66 : 3539–3554.
33. NakayamaK, FrewIJ, HagensenM, SkalsM, HabelhahH, et al. (2004) Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell 117 : 941–952.
34. NakayamaK, GazdoiuS, AbrahamR, PanZQ, RonaiZ (2007) Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. Biochem J 401 : 217–226.
35. QiJ, NakayamaK, CardiffRD, BorowskyAD, KaulK, et al. (2010) Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell 18 : 23–38.
36. AhmedAU, SchmidtRL, ParkCH, ReedNR, HesseSE, et al. (2008) Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth. J Natl Cancer Inst 100 : 1606–1629.
37. MollerA, HouseCM, WongCS, ScanlonDB, LiuMC, et al. (2009) Inhibition of Siah ubiquitin ligase function. Oncogene 28 : 289–296.
38. SchmidtRL, ParkCH, AhmedAU, GundelachJH, ReedNR, et al. (2007) Inhibition of RAS-mediated transformation and tumorigenesis by targeting the downstream E3 ubiquitin ligase seven in absentia homologue. Cancer Res 67 : 11798–11810.
39. AmsonRB, NemaniM, RoperchJP, IsraeliD, BougueleretL, et al. (1996) Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the drosophila seven in absentia gene. Proc Natl Acad Sci U S A 93 : 3953–3957.
40. MatsuzawaS, TakayamaS, FroeschBA, ZapataJM, ReedJC (1998) p53-inducible human homologue of Drosophila seven in absentia (Siah) inhibits cell growth: suppression by BAG-1. EMBO J 17 : 2736–2747.
41. McCluneS, McKayAC, WrightPM, PattersonCC, ClarkeRS (1992) Synergistic interaction between midazolam and propofol. Br J Anaesth 69 : 240–245.
42. MatsuzawaSI, ReedJC (2001) Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol Cell 7 : 915–926.
43. RenekerLW, ChenH, OverbeekPA (2011) Activation of unfolded protein response in transgenic mouse lenses. Invest Ophthalmol Vis Sci 52 : 2100–2108.
44. UranoF, WangX, BertolottiA, ZhangY, ChungP, et al. (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287 : 664–666.
45. KoditzJ, NesperJ, WottawaM, StiehlDP, CamenischG, et al. (2007) Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 110 : 3610–3617.
46. HabelhahH, FrewIJ, LaineA, JanesPW, RelaixF, et al. (2002) Stress-induced decrease in TRAF2 stability is mediated by Siah2. EMBO J 21 : 5756–5765.
47. MaY, BrewerJW, DiehlJA, HendershotLM (2002) Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318 : 1351–1365.
48. FelsDR, KoumenisC (2006) The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther 5 : 723–728.
49. Dalton-GriffinL, WilsonSJ, KellamP (2009) X-box binding protein 1 contributes to induction of the Kaposi's sarcoma-associated herpesvirus lytic cycle under hypoxic conditions. J Virol 83 : 7202–7209.
50. KamimuraD, BevanMJ (2008) Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection. J Immunol 181 : 5433–5441.
51. JoyceMA, WaltersKA, LambSE, YehMM, ZhuLF, et al. (2009) HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog 5: e1000291.
52. MerquiolE, UziD, MuellerT, GoldenbergD, NahmiasY, et al. (2011) HCV causes chronic endoplasmic reticulum stress leading to adaptation and interference with the unfolded protein response. PLoS One 6: e24660.
53. HiwatashiY, KannoK, TakasakiC, GoryoK, SatoT, et al. (2011) PHD1 interacts with ATF4 and negatively regulates its transcriptional activity without prolyl hydroxylation. Exp Cell Res 317 : 2789–2799.
54. NatarajanR, SalloumFN, FisherBJ, SmithsonL, AlmenaraJ, et al. (2009) Prolyl hydroxylase inhibition attenuates post-ischemic cardiac injury via induction of endoplasmic reticulum stress genes. Vascul Pharmacol 51 : 110–118.
55. MalhotraJD, MiaoH, ZhangK, WolfsonA, PennathurS, et al. (2008) Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc Natl Acad Sci U S A 105 : 18525–18530.
56. LeeAS (2007) GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 67 : 3496–3499.
57. LeeAS, HendershotLM (2006) ER stress and cancer. Cancer Biol Ther 5 : 721–722.
58. RankinEB, GiacciaAJ (2008) The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 15 : 678–685.
59. ScrivenP, CoulsonS, HainesR, BalasubramanianS, CrossS, et al. (2009) Activation and clinical significance of the unfolded protein response in breast cancer. Br J Cancer 101 : 1692–1698.
60. SemenzaGL (2008) Tumor metabolism: cancer cells give and take lactate. J Clin Invest 118 : 3835–3837.
61. WilliamsKJ, TelferBA, AirleyRE, PetersHP, SheridanMR, et al. (2002) A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis. Oncogene 21 : 282–290.
62. YeJ, KoumenisC (2009) ATF4, an ER stress and hypoxia-inducible transcription factor and its potential role in hypoxia tolerance and tumorigenesis. Curr Mol Med 9 : 411–416.
63. TangX, LucasJE, ChenJL, LaMonteG, WuJ, et al. (2012) Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs. Cancer Res 72 : 491–502.
64. ThomasJD, DiasLM, JohannesGJ (2008) Translational repression during chronic hypoxia is dependent on glucose levels. RNA 14 : 771–781.
65. ShibataM, HattoriH, SasakiT, GotohJ, HamadaJ, et al. (2003) Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice. Neuroscience 118 : 491–499.
66. MorimotoN, OidaY, ShimazawaM, MiuraM, KudoT, et al. (2007) Involvement of endoplasmic reticulum stress after middle cerebral artery occlusion in mice. Neuroscience 147 : 957–967.
67. BiglioliP, ArenaV, Della BellaP, SusiniG, TondoC, et al. (1991) [The surgical treatment of pre-excitation syndromes]. Cardiologia 36 : 485–495.
68. BoumanL, SchlierfA, LutzAK, ShanJ, DeinleinA, et al. (2011) Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ 18 : 769–782.
69. ShangJ, LiuN, TanakaN, AbeK (2012) Expressions of hypoxic stress sensor proteins after transient cerebral ischemia in mice. J Neurosci Res 90 : 648–655.
70. Al-RawashdehFY, ScrivenP, CameronIC, VerganiPV, WyldL (2010) Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 22 : 1099–1105.
71. BadiolaN, PenasC, Minano-MolinaA, Barneda-ZahoneroB, FadoR, et al. (2011) Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12. Cell Death Dis 2: e149.
72. BenavidesA, PastorD, SantosP, TranqueP, CalvoS (2005) CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose deprivation. Glia 52 : 261–275.
73. SzegezdiE, DuffyA, O'MahoneyME, LogueSE, MylotteLA, et al. (2006) ER stress contributes to ischemia-induced cardiomyocyte apoptosis. Biochem Biophys Res Commun 349 : 1406–1411.
74. ZhangA, ZhangJ, SunP, YaoC, SuC, et al. (2010) EIF2alpha and caspase-12 activation are involved in oxygen-glucose-serum deprivation/restoration-induced apoptosis of spinal cord astrocytes. Neurosci Lett 478 : 32–36.
75. FrewIJ, HammondVE, DickinsRA, QuinnJM, WalkleyCR, et al. (2003) Generation and analysis of Siah2 mutant mice. Mol Cell Biol 23 : 9150–9161.
76. MasuokaHC, TownesTM (2002) Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood 99 : 736–745.
77. DlugoszAA, GlickAB, TennenbaumT, WeinbergWC, YuspaSH (1995) Isolation and utilization of epidermal keratinocytes for oncogene research. Methods Enzymol 254 : 3–20.
78. MaL, TaoY, DuranA, LladoV, GalvezA, et al. (2013) Control of nutrient stress-induced metabolic reprogramming by PKCzeta in tumorigenesis. Cell 152 : 599–611.
79. HabelhahH, LaineA, Erdjument-BromageH, TempstP, GershwinME, et al. (2004) Regulation of 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah. J Biol Chem 279 : 53782–53788.
80. MakinoY, CaoR, SvenssonK, BertilssonG, AsmanM, et al. (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414 : 550–554.
81. MakinoY, KanopkaA, WilsonWJ, TanakaH, PoellingerL (2002) Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J Biol Chem 277 : 32405–32408.
82. LangePS, ChavezJC, PintoJT, CoppolaG, SunCW, et al. (2008) ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med 205 : 1227–1242.
83. ParkSW, ZhouY, LeeJ, LuA, SunC, et al. (2010) The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med 16 : 429–437.
84. SmythGK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.
85. BenjaminiY, HochbergY (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B, Statistical methodology 57 : 289–300.
86. GentlemanRC, CareyVJ, BatesDM, BolstadB, DettlingM, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80.
87. SubramanianA, TamayoP, MoothaVK, MukherjeeS, EbertBL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102 : 15545–15550.
88. DouglasRM, ChenAH, IniguezA, WangJ, FuZ, et al. (2013) Chemokine receptor-like 2 is involved in ischemic brain injury. J Exp Stroke Transl Med 6 : 1–6.
Štítky
Genetika Reprodukčná medicína
Článek Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin PathwayČlánek Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human DiseasesČlánek G×G×E for Lifespan in : Mitochondrial, Nuclear, and Dietary Interactions that Modify LongevityČlánek PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial MatrixČlánek Rapid Evolution of PARP Genes Suggests a Broad Role for ADP-Ribosylation in Host-Virus ConflictsČlánek The Impact of Population Demography and Selection on the Genetic Architecture of Complex TraitsČlánek Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar AcidificationČlánek The Case for Junk DNA
Článok vyšiel v časopisePLOS Genetics
Najčítanejšie tento týždeň
2014 Číslo 5- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
-
Všetky články tohto čísla
- Genetic Interactions Involving Five or More Genes Contribute to a Complex Trait in Yeast
- A Mutation in the Gene in Dogs with Hereditary Footpad Hyperkeratosis (HFH)
- Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling
- Heterogeneity in the Frequency and Characteristics of Homologous Recombination in Pneumococcal Evolution
- Genome-Wide Nucleosome Positioning Is Orchestrated by Genomic Regions Associated with DNase I Hypersensitivity in Rice
- Null Mutation in PGAP1 Impairing Gpi-Anchor Maturation in Patients with Intellectual Disability and Encephalopathy
- Single Nucleotide Variants in Transcription Factors Associate More Tightly with Phenotype than with Gene Expression
- Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway
- Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases
- Epistatically Interacting Substitutions Are Enriched during Adaptive Protein Evolution
- Meiotic Drive Impacts Expression and Evolution of X-Linked Genes in Stalk-Eyed Flies
- G×G×E for Lifespan in : Mitochondrial, Nuclear, and Dietary Interactions that Modify Longevity
- Population Genomic Analysis of Ancient and Modern Genomes Yields New Insights into the Genetic Ancestry of the Tyrolean Iceman and the Genetic Structure of Europe
- p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision
- Whole Exome Re-Sequencing Implicates and Cilia Structure and Function in Resistance to Smoking Related Airflow Obstruction
- Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues
- R-loops Associated with Triplet Repeat Expansions Promote Gene Silencing in Friedreich Ataxia and Fragile X Syndrome
- PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial Matrix
- The Impairment of MAGMAS Function in Human Is Responsible for a Severe Skeletal Dysplasia
- Octopamine Neuromodulation Regulates Gr32a-Linked Aggression and Courtship Pathways in Males
- Mlh2 Is an Accessory Factor for DNA Mismatch Repair in
- Activating Transcription Factor 6 Is Necessary and Sufficient for Alcoholic Fatty Liver Disease in Zebrafish
- The Spatiotemporal Program of DNA Replication Is Associated with Specific Combinations of Chromatin Marks in Human Cells
- Rapid Evolution of PARP Genes Suggests a Broad Role for ADP-Ribosylation in Host-Virus Conflicts
- Genome-Wide Inference of Ancestral Recombination Graphs
- Mutations in Four Glycosyl Hydrolases Reveal a Highly Coordinated Pathway for Rhodopsin Biosynthesis and N-Glycan Trimming in
- SHP2 Regulates Chondrocyte Terminal Differentiation, Growth Plate Architecture and Skeletal Cell Fates
- The Impact of Population Demography and Selection on the Genetic Architecture of Complex Traits
- Retinoid-X-Receptors (α/β) in Melanocytes Modulate Innate Immune Responses and Differentially Regulate Cell Survival following UV Irradiation
- Genetic Dissection of the Female Head Transcriptome Reveals Widespread Allelic Heterogeneity
- Genome Sequencing and Comparative Genomics of the Broad Host-Range Pathogen AG8
- Copy Number Variation Is a Fundamental Aspect of the Placental Genome
- GOLPH3 Is Essential for Contractile Ring Formation and Rab11 Localization to the Cleavage Site during Cytokinesis in
- Hox Transcription Factors Access the RNA Polymerase II Machinery through Direct Homeodomain Binding to a Conserved Motif of Mediator Subunit Med19
- Drosha Promotes Splicing of a Pre-microRNA-like Alternative Exon
- Predicting the Minimal Translation Apparatus: Lessons from the Reductive Evolution of
- PAX6 Regulates Melanogenesis in the Retinal Pigmented Epithelium through Feed-Forward Regulatory Interactions with MITF
- Enhanced Interaction between Pseudokinase and Kinase Domains in Gcn2 stimulates eIF2α Phosphorylation in Starved Cells
- A HECT Ubiquitin-Protein Ligase as a Novel Candidate Gene for Altered Quinine and Quinidine Responses in
- dGTP Starvation in Provides New Insights into the Thymineless-Death Phenomenon
- Phosphorylation Modulates Clearance of Alpha-Synuclein Inclusions in a Yeast Model of Parkinson's Disease
- RPM-1 Uses Both Ubiquitin Ligase and Phosphatase-Based Mechanisms to Regulate DLK-1 during Neuronal Development
- More of a Good Thing or Less of a Bad Thing: Gene Copy Number Variation in Polyploid Cells of the Placenta
- More of a Good Thing or Less of a Bad Thing: Gene Copy Number Variation in Polyploid Cells of the Placenta
- Heritable Transmission of Stress Resistance by High Dietary Glucose in
- Revertant Mutation Releases Confined Lethal Mutation, Opening Pandora's Box: A Novel Genetic Pathogenesis
- Lifespan Extension by Methionine Restriction Requires Autophagy-Dependent Vacuolar Acidification
- A Genome-Wide Assessment of the Role of Untagged Copy Number Variants in Type 1 Diabetes
- Selectivity in Genetic Association with Sub-classified Migraine in Women
- A Lack of Parasitic Reduction in the Obligate Parasitic Green Alga
- The Proper Splicing of RNAi Factors Is Critical for Pericentric Heterochromatin Assembly in Fission Yeast
- Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma
- Six Homeoproteins and a linc-RNA at the Fast MYH Locus Lock Fast Myofiber Terminal Phenotype
- EDR1 Physically Interacts with MKK4/MKK5 and Negatively Regulates a MAP Kinase Cascade to Modulate Plant Innate Immunity
- Genes That Bias Mendelian Segregation
- The Case for Junk DNA
- An In Vivo EGF Receptor Localization Screen in Identifies the Ezrin Homolog ERM-1 as a Temporal Regulator of Signaling
- Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder
- Hyperactivated Wnt Signaling Induces Synthetic Lethal Interaction with Rb Inactivation by Elevating TORC1 Activities
- Mutations in the Cholesterol Transporter Gene Are Associated with Excessive Hair Overgrowth
- Scribble Modulates the MAPK/Fra1 Pathway to Disrupt Luminal and Ductal Integrity and Suppress Tumour Formation in the Mammary Gland
- A Novel CH Transcription Factor that Regulates Expression Interdependently with GliZ in
- Phosphorylation of a WRKY Transcription Factor by MAPKs Is Required for Pollen Development and Function in
- Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics
- Spermatid Cyst Polarization in Depends upon and the CPEB Family Translational Regulator
- Insights into the Genetic Structure and Diversity of 38 South Asian Indians from Deep Whole-Genome Sequencing
- Intron Retention in the 5′UTR of the Novel ZIF2 Transporter Enhances Translation to Promote Zinc Tolerance in
- A Dominant-Negative Mutation of Mouse Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation
- Biased, Non-equivalent Gene-Proximal and -Distal Binding Motifs of Orphan Nuclear Receptor TR4 in Primary Human Erythroid Cells
- Ras-Mediated Deregulation of the Circadian Clock in Cancer
- Retinoic Acid-Related Orphan Receptor γ (RORγ): A Novel Participant in the Diurnal Regulation of Hepatic Gluconeogenesis and Insulin Sensitivity
- Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions
- Fine Tuning of the UPR by the Ubiquitin Ligases Siah1/2
- Paternal Poly (ADP-ribose) Metabolism Modulates Retention of Inheritable Sperm Histones and Early Embryonic Gene Expression
- Allele-Specific Genome-wide Profiling in Human Primary Erythroblasts Reveal Replication Program Organization
- PLOS Genetics
- Archív čísel
- Aktuálne číslo
- Informácie o časopise
Najčítanejšie v tomto čísle- PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial Matrix
- Null Mutation in PGAP1 Impairing Gpi-Anchor Maturation in Patients with Intellectual Disability and Encephalopathy
- Phosphorylation of a WRKY Transcription Factor by MAPKs Is Required for Pollen Development and Function in
- p53 Requires the Stress Sensor USF1 to Direct Appropriate Cell Fate Decision
Prihlásenie#ADS_BOTTOM_SCRIPTS#Zabudnuté hesloZadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
- Časopisy