Stanley Tahara, PhD

Associate Professor of Molecular Microbiology & Immunology

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Overview

Our laboratory is interested in post-transcriptional regulation. Currently we study miRNA synthesis and function in the sickle cell disease model. Clinical consequences of this genetic illness lead to a spectrum of circulatory and respiratory symptoms originating from a single mutation of the beta-globin gene. In particular pulmonary hypertension results from the vascular occlusion caused by the abnormal red blood cell shape. This leads to expression of vasoactive cytokines and hormones which aggravate and prolong the original vascular insult. Plasminogen activator inhibitor-1 (SERPINE1) and endothelin 1 (EDN1) are two such cell modulators that are dysregulated in acute phases of the illness. We identified miRNAs which are responsible for reversing expression of both SERPINE1 and EDN1; more importantly, we examined in detail the transcriptional regulation and synthesis of these key miRNA mediators. This information has been useful in that we identified a potential pharmacologic therapy that induced specific miRNA expression for the purpose of reducing the expression of SERPINE1 and EDN1.

The second area of interest examines the biological significance of protein arginine methylation of translation initiation factors. We are currently studying the effect of Arg362 methylation of factor eIF4A. The latter is the prototype of DEXD/H box nucleotide dependent helicases. We have found that methylation of Arg362 results in 1) significantly reduced ATPase activity and 2) inhibition of eIF4A assembly with eIF4G into the eIF4F heterotrimer. We believe this example of covalent modification is representative of a previously unknown regulatory circuit for modulating cellular protein synthesis. Our current efforts are directed towards identifying regulators of protein methylation and further examination of eIF4A with respect to mRNA specific effects in protein synthesis.

Publications

  • Protocol for generation of humanized HCC mouse model and cancer-driver mutations using CRISPR-Cas9 STAR Protoc. 2023 Dec 08; 4(4):102389. . View in PubMed
  • Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal iScience. 2023 Jul 21; 26(7):107035. . View in PubMed
  • MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells Cell Death Discov. 2023 Apr 28; 9(1):141. . View in PubMed
  • LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells iScience. 2023 Mar 17; 26(3):106254. . View in PubMed
  • Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor-Initiating Stem-Like Cells Adv Sci (Weinh). 2023 05; 10(14):e2206812. . View in PubMed
  • ß-CATENIN stabilizes HIF2 through lncRNA and inhibits intravenous immunoglobulin immunotherapy Front Immunol. 2023; 14:1204907. . View in PubMed
  • Intranasal Delivery of miR133b in a NEO100-Based Formulation Induces a Healing Response in Spinal Cord-Injured Mice Cells. 2023 03 18; 12(6). . View in PubMed
  • Gut-derived Endotoxin-TLR4 Signaling Drives MYC-Ig Translocation to Promote Lymphoproliferation through c-JUN and STAT3 Activation Mol Cancer Res. 2023 02 01; 21(2):155-169. . View in PubMed
  • c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity iScience. 2022 Jun 17; 25(6):104325. . View in PubMed
  • Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells Cancers (Basel). 2022 May 12; 14(10). . View in PubMed
  • Intravenous delivery of microRNA-133b along with Argonaute-2 enhances spinal cord recovery following cervical contusion in mice Spine J. 2020 07; 20(7):1138-1151. . View in PubMed
  • p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs Nat Commun. 2020 06 17; 11(1):3084. . View in PubMed
  • Placenta growth factor mediated gene regulation in sickle cell disease Blood Rev. 2018 01; 32(1):61-70. . View in PubMed
  • Hepatitis C virus has a genetically determined lymphotropism through co-receptor B72. Nat Commun. 2017 01 09; 8:13882. . View in PubMed
  • NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism Cell Metab. 2016 Jan 12; 23(1):206-19. . View in PubMed
  • Activated Transcription Factor 3 in Association with Histone Deacetylase 6 Negatively Regulates MicroRNA 199a2 Transcription by Chromatin Remodeling and Reduces Endothelin-1 Expression Mol Cell Biol. 2016 11 15; 36(22):2838-2854. . View in PubMed
  • Peroxisome proliferator-activated receptor-a-mediated transcription of miR-301a and miR-454 and their host gene SKA2 regulates endothelin-1 and PAI-1 expression in sickle cell disease Biosci Rep. 2015 Oct 12; 35(6). . View in PubMed
  • Erythropoietin-mediated expression of placenta growth factor is regulated via activation of hypoxia-inducible factor-1a and post-transcriptionally by miR-214 in sickle cell disease Biochem J. 2015 Jun 15; 468(3):409-23. . View in PubMed
  • MicroRNA 648 Targets ET-1 mRNA and is cotranscriptionally regulated with MICAL3 by PAX5 Mol Cell Biol. 2015 Feb; 35(3):514-28. . View in PubMed
  • Peroxisome proliferator-activated receptor-a-mediated transcription of miR-199a2 attenuates endothelin-1 expression via hypoxia-inducible factor-1a J Biol Chem. 2014 Dec 26; 289(52):36031-47. . View in PubMed
  • Argonaute-2 promotes miR-18a entry in human brain endothelial cells J Am Heart Assoc. 2014 May 16; 3(3):e000968. . View in PubMed
  • MicroRNA-18a improves human cerebral arteriovenous malformation endothelial cell function Stroke. 2014 Jan; 45(1):293-7. . View in PubMed
  • Proteasome inhibition induces both antioxidant and hb f responses in sickle cell disease via the nrf2 pathway Hemoglobin. 2014; 38(3):188-95. . View in PubMed
  • Contextual effect of repression of bone morphogenetic protein activity in prostate cancer Endocr Relat Cancer. 2013 Dec; 20(6):861-74. . View in PubMed
  • Involvement of miR-30c and miR-301a in immediate induction of plasminogen activator inhibitor-1 by placental growth factor in human pulmonary endothelial cells Biochem J. 2011 Mar 15; 434(3):473-82. . View in PubMed
  • Substrate profiling of PRMT1 reveals amino acid sequences that extend beyond the “RGG” paradigm Biochemistry. 2008 Sep 09; 47(36):9456-66. . View in PubMed
  • Reduced phagocytosis of colloidal carriers using soluble CD47 Pharm Res. 2003 Oct; 20(10):1539-42. . View in PubMed
  • High affinity interaction between nucleocapsid protein and leader/intergenic sequence of mouse hepatitis virus RNA J Gen Virol. 2000 Jan; 81(Pt 1):181-8. . View in PubMed
  • The 3′-untranslated region of hepatitis C virus RNA enhances translation from an internal ribosomal entry site J Virol. 1998 Nov; 72(11):8789-96. . View in PubMed
  • Variability of persisting MHV RNA sequences constituting immune and replication-relevant domains Virology. 1998 May 10; 244(2):563-72. . View in PubMed
  • Mouse hepatitis virus nucleocapsid protein as a translational effector of viral mRNAs Adv Exp Med Biol. 1998; 440:313-8. . View in PubMed
  • Differential expression of the murine eukaryotic translation initiation factor isogenes eIF4A(I) and eIF4A(II) is dependent upon cellular growth status Arch Biochem Biophys. 1997 Feb 01; 338(1):111-20. . View in PubMed
  • Tumor necrosis factor expression during mouse hepatitis virus-induced demyelinating encephalomyelitis J Virol. 1995 Sep; 69(9):5898-903. . View in PubMed
  • Transcription and translation of proinflammatory cytokines following JHMV infection Adv Exp Med Biol. 1995; 380:173-8. . View in PubMed
  • Modulation of cellular macromolecular synthesis by coronavirus: implication for pathogenesis J Virol. 1994 Oct; 68(10):6815-9. . View in PubMed
  • Coronavirus translational regulation: leader affects mRNA efficiency Virology. 1994 Aug 01; 202(2):621-30. . View in PubMed
  • Expression of rat liver reduced glutathione transport in Xenopus laevis oocytes J Biol Chem. 1993 Feb 05; 268(4):2324-8. . View in PubMed
  • Effects of mouse hepatitis virus infection on host cell metabolism Adv Exp Med Biol. 1993; 342:111-6. . View in PubMed
  • Effect of eukaryotic initiation factor 4F on AUG selection in a bicistronic mRNA J Biol Chem. 1991 Feb 25; 266(6):3594-601. . View in PubMed
  • Preferred translation of human hepatitis B virus polymerase from core protein- but not from precore protein-specific transcript J Virol. 1990 Sep; 64(9):4578-81. . View in PubMed
  • Inhibition of eukaryotic translation by nucleoside 5′-monophosphate analogues of mRNA 5′-cap: changes in N7 substituent affect analogue activity Biochemistry. 1989 May 30; 28(11):4771-8. . View in PubMed
  • Beta-globin mRNAs capped with m7G, m27(2)G or m2. 2. 7(3)G differ in intrinsic translation efficiency. Nucleic Acids Res. 1988 Sep 26; 16(18):8953-62. . View in PubMed
  • Inhibition of eukaryotic translation by analogues of messenger RNA 5′-cap: chemical and biological consequences of 5′-phosphate modifications of 7-methylguanosine 5′-monophosphate Biochemistry. 1987 Jul 14; 26(14):4372-80. . View in PubMed