Biopolym. Cell. 2018; 34(6):411-425.
http://dx.doi.org/10.7124/bc.00098C
Reviews
Control of the amount and functionality of the eEF1A1 and eEF1A2 isoforms in mammalian cells
1Negrutskii B. S., 1Novosylna O. V., 1Porubleva L. V., 1Vislovukh A. A.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143

Abstract

Aim. To review mechanisms of regulation of expression and the functionality of two isoforms of translation elongation factor eEF1A in mammalian cells. Results. eEF1A1 and eEF1A2 proteins are regulated by post-translational modifications, protein-protein and protein-tRNA interactions as well as by controlling the amount of their mRNAs in human cells. Conclusions. EEF1A1 mRNA levels in cancer cells may depend on the allelic copy number while the level of EEF1A2 mRNA may be controlled by micro RNAs. eEF1A2 protein activity in different cellular processes may be determined, in part, by its increased affinity for tRNA and viral RNAs as compared to eEF1A1. eEF1A1 activity can be regulated by its increased susceptibility to post-translational modifications (PTM) and protein-protein interactions (PTI) as compared to eEF1A2.
Keywords: Translation elongation factors, regulation, protein isoforms
Full text: (PDF, in English)

References

[1] El'skaya AV, Negrutskii BS, Shalak V, Vislovukh A, Vlasenko D, Novosylna A, Lukash T, Veremieva M. Specific features of protein biosynthesis in higher eukaryotes. Biopolym Cell. 2013; 29(3): 177-87.
[2] Abbott CM, Newbery HJ, Squires CE, Brownstein D, Griffiths LA, Soares DC. eEF1A2 and neuronal degeneration. Biochem Soc Trans. 2009;37(Pt 6):1293-7.
[3] Novosylna O. Protein isoforms. Origin, structure and functions. Biopolym Cell. 2017; 33(3): 161–71.
[4] Mishra AK, Gangwani L, Davis RJ, Lambright DG. Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes. Proc Natl Acad Sci U S A. 2007;104(35):13930-5.
[5] Bandyopadhyay U, Sridhar S, Kaushik S, Kiffin R, Cuervo AM. Identification of regulators of chaperone-mediated autophagy. Mol Cell. 2010;39(4):535-47.
[6] Chang R, Wang E. Mouse translation elongation factor eEF1A-2 interacts with Prdx-I to protect cells against apoptotic death induced by oxidative stress. J Cell Biochem. 2007;100(2):267-78.
[7] Borradaile NM, Buhman KK, Listenberger LL, Magee CJ, Morimoto ET, Ory DS, Schaffer JE. A critical role for eukaryotic elongation factor 1A-1 in lipotoxic cell death. Mol Biol Cell. 2006;17(2):770-8.
[8] Lukash TO, Turkivska HV, Negrutskii BS, El'skaya AV. Chaperone-like activity of mammalian elongation factor eEF1A: renaturation of aminoacyl-tRNA synthetases. Int J Biochem Cell Biol. 2004;36(7):1341-7.
[9] Ransom-Hodgkins WD, Brglez I, Wang X, Boss WF. Calcium-regulated proteolysis of eEF1A. Plant Physiol. 2000;122(3):957-65.
[10] Tarrant DJ, Stirpe M, Rowe M, Howard MJ, von der Haar T, Gourlay CW. Inappropriate expression of the translation elongation factor 1A disrupts genome stability and metabolism. J Cell Sci. 2016;129(24):4455-4465.
[11] Tash JS, Attardi B, Hild SA, Chakrasali R, Jakkaraj SR, Georg GI. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose. Biol Reprod. 2008;78(6):1127-38.
[12] Jeganathan S, Morrow A, Amiri A, Lee JM. Eukaryotic elongation factor 1A2 cooperates with phosphatidylinositol-4 kinase III beta to stimulate production of filopodia through increased phosphatidylinositol-4,5 bisphosphate generation. Mol Cell Biol. 2008;28(14):4549-61.
[13] Goulart-Silva F, Serrano-Nascimento C, Nunes MT. Hypothyroidism decreases proinsulin gene expression and the attachment of its mRNA and eEF1A protein to the actin cytoskeleton of INS-1E cells. Braz J Med Biol Res. 2011;44(10):1060-7.
[14] Gross SR, Kinzy TG. Translation elongation factor 1A is essential for regulation of the actin cytoskeleton and cell morphology. Nat Struct Mol Biol. 2005;12(9):772-8.
[15] Abbas W, Kumar A, Herbein G. The eEF1A Proteins: At the Crossroads of Oncogenesis, Apoptosis, and Viral Infections. Front Oncol. 2015;5:75.
[16] Tomlinson VA, Newbery HJ, Wray NR, Jackson J, Larionov A, Miller WR, Dixon JM, Abbott CM. Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours. BMC Cancer. 2005;5:113.
[17] Anand N, Murthy S, Amann G, Wernick M, Porter LA, Cukier IH, Collins C, Gray JW, Diebold J, Demetrick DJ, Lee JM. Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nat Genet. 2002;31(3):301-5.
[18] Lin CY, Beattie A, Baradaran B, Dray E, Duijf PHG. Contradictory mRNA and protein misexpression of EEF1A1 in ductal breast carcinoma due to cell cycle regulation and cellular stress. Sci Rep. 2018;8(1):13904.
[19] Hassan MK, Kumar D, Naik M, Dixit M. The expression profile and prognostic significance of eukaryotic translation elongation factors in different cancers. PLoS One. 2018;13(1):e0191377.
[20] Vislovukh AA, Gralievska NL, Naumovets MG, Negrutskii BS, El'skaya AV. mRNAs coding for A1 and A2 isoforms of translation factor eEF1A demonstrate different half-lives while A1 and A2 proteins are similarly stable in MCF7 cells. Biopolym Cell. 2013; 29(5): 389-94.
[21] Vislovukh AA, Naumovets MG, Kovalenko MI, Groisman RS, Groisman IS, Negrutskii BS, El'skaya AV. Isoforms of elongation factor eEF1A may be differently regulated at post-transcriptional level in breast cancer progression. Biopolym Cell. 2013; 29(1): 55-63.
[22] Vislovukh A, Groisman I, El’skaya A, Negrutskii B, Polesskaya A. Transcriptional and post-transcriptional control of eEF1A2 expression during myoblast diffrerentiation. Biopolym Cell. 2012; 28(6): 456-60.
[23] Vislovukh A, Kratassiouk G, Porto E, Gralievska N, Beldiman C, Pinna G, El'skaya A, Harel-Bellan A, Negrutskii B, Groisman I. Proto-oncogenic isoform A2 of eukaryotic translation elongation factor eEF1 is a target of miR-663 and miR-744. Br J Cancer. 2013;108(11):2304-11.
[24] Zang W, Wang Y, Wang T, Du Y, Chen X, Li M, Zhao G. miR-663 attenuates tumor growth and invasiveness by targeting eEF1A2 in pancreatic cancer. Mol Cancer. 2015;14:37.
[25] Chen Q, Zhao T, Xie X, Yu D, Wu L, Yu W, Sun W. MicroRNA-663 regulates the proliferation of fibroblasts in hypertrophic scars via transforming growth factor-β1. Exp Ther Med. 2018;16(2):1311-1317.
[26] Fiori ME, Villanova L, Barbini C, De Angelis ML, De Maria R. miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2. Cell Death Dis. 2018;9(2):49.
[27] Liang S, Zhang N, Deng Y, Chen L, Zhang Y, Zheng Z, Luo W, Lv Z, Li S, Xu T. miR-663 promotes NPC cell proliferation by directly targeting CDKN2A. Mol Med Rep. 2017;16(4):4863-4870.
[28] Kleemann M, Schneider H, Unger K, Sander P, Schneider EM, Fischer-Posovszky P, Handrick R, Otte K. MiR-744-5p inducing cell death by directly targeting HNRNPC and NFIX in ovarian cancer cells. Sci Rep. 2018;8(1):9020.
[29] Shen J, Li M. MicroRNA-744 inhibits cellular proliferation and invasion of colorectal cancer by directly targeting oncogene Notch1. Oncol Res. 2018 Feb 22.
[30] Li JZ, Gao W, Lei WB, Zhao J, Chan JY, Wei WI, Ho WK, Wong TS. MicroRNA 744-3p promotes MMP-9-mediated metastasis by simultaneously suppressing PDCD4 and PTEN in laryngeal squamous cell carcinoma. Oncotarget. 2016;7(36):58218-58233.
[31] Yaremchuk A, Shalak VF, Novosylna OV, Negrutskii BS, Crépin T, El'skaya AV, Tukalo M. Purification, crystallization and preliminary X-ray crystallographic analysis of mammalian translation elongation factor eEF1A2. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012;68(Pt 3):295-7.
[32] Crepin T, Shalak VF, Yaremchuk AD, Vlasenko DO, McCarthy A, Negrutskii BS, Tukalo MA, El'skaya AV. Mammalian translation elongation factor eEF1A2: X-ray structure and new features of GDP/GTP exchange mechanism in higher eukaryotes. Nucleic Acids Res. 2014;42(20):12939-48.
[33] Negrutskii B, Vlasenko D, El'skaya A. From global phosphoproteomics to individual proteins: the case of translation elongation factor eEF1A. Expert Rev Proteomics. 2012;9(1):71-83.
[34] Sanges C, Scheuermann C, Zahedi RP, Sickmann A, Lamberti A, Migliaccio N, Baljuls A, Marra M, Zappavigna S, Reinders J, Rapp U, Abbruzzese A, Caraglia M, Arcari P. Raf kinases mediate the phosphorylation of eukaryotic translation elongation factor 1A and regulate its stability in eukaryotic cells. Cell Death Dis. 2012;3:e276. Erratum in: Cell Death Dis. 2012;3:e317.
[35] Vlasenko DO, Novosylna OV, Negrutskii BS, El'skaya AV. Truncation of the A,A(*),A' helices segment impairs the actin bundling activity of mammalian eEF1A1. FEBS Lett. 2015;589(11):1187-93.
[36] Sánchez-Murcia PA, Cortés-Cabrera Á, Gago F. Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B. J Comput Aided Mol Des. 2017;31(10):915-928.
[37] Hamey JJ, Wilkins MR. Methylation of Elongation Factor 1A: Where, Who, and Why? Trends Biochem Sci. 2018;43(3):211-223.
[38] Jakobsson ME, Małecki JM, Halabelian L, Nilges BS, Pinto R, Kudithipudi S, Munk S, Davydova E, Zuhairi FR, Arrowsmith CH, Jeltsch A, Leidel SA, Olsen JV, Falnes PØ. The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates. Nat Commun. 2018;9(1):3411.
[39] Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL. Regulation of cellular metabolism by protein lysine acetylation. Science. 2010;327(5968):1000-4.
[40] Grimes M, Hall B, Foltz L, Levy T, Rikova K, Gaiser J, Cook W, Smirnova E, Wheeler T, Clark NR, Lachmann A, Zhang B, Hornbeck P, Ma'ayan A, Comb M. Integration of protein phosphorylation, acetylation, and methylation data sets to outline lung cancer signaling networks. Sci Signal. 2018;11(531). pii: eaaq1087.
[41] Jakobsson ME, Małecki J, Falnes PØ. Regulation of eukaryotic elongation factor 1 alpha (eEF1A) by dynamic lysine methylation. RNA Biol. 2018;15(3):314-319.
[42] Wang T, Birsoy K, Hughes NW, Krupczak KM, Post Y, Wei JJ, Lander ES, Sabatini DM. Identification and characterization of essential genes in the human genome. Science. 2015;350(6264):1096-101.
[43] Malecki J, Aileni VK, Ho AYY, Schwarz J, Moen A, Sørensen V, Nilges BS, Jakobsson ME, Leidel SA, Falnes PØ. The novel lysine specific methyltransferase METTL21B affects mRNA translation through inducible and dynamic methylation of Lys-165 in human eukaryotic elongation factor 1 alpha (eEF1A). Nucleic Acids Res. 2017;45(8):4370-4389.
[44] Jakobsson ME, Malecki J, Nilges BS, Moen A, Leidel SA, Falnes PØ. Methylation of human eukaryotic elongation factor alpha (eEF1A) by a member of a novel protein lysine methyltransferase family modulates mRNA translation. Nucleic Acids Res. 2017;45(14):8239-8254.
[45] Behrmann E, Loerke J, Budkevich TV, Yamamoto K, Schmidt A, Penczek PA, Vos MR, Bürger J, Mielke T, Scheerer P, Spahn CM. Structural snapshots of actively translating human ribosomes. Cell. 2015;161(4):845-57.
[46] De Melo J, He L, Tang D. The protein-protein interaction-mediated inactivation of PTEN. Curr Mol Med. 2014;14(1):22-33.
[47] Oladimeji P, Cui H, Zhang C, Chen T. Regulation of PXR and CAR by protein-protein interaction and signaling crosstalk. Expert Opin Drug Metab Toxicol. 2016;12(9):997-1010.
[48] Jubb HC, Pandurangan AP, Turner MA, Ochoa-Montaño B, Blundell TL, Ascher DB. Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health. Prog Biophys Mol Biol. 2017;128:3-13.
[49] Draime A, Bridoux L, Belpaire M, Pringels T, Tys J, Rezsohazy R. PRDM14, a putative histone methyl-transferase, interacts with and decreases the stability and activity of the HOXA1 transcription factor. Biochim Biophys Acta Gene Regul Mech. 2018;1861(5):534-542.
[50] Qi W, Manfield IW, Muench SP, Baker A. AtSPX1 affects the AtPHR1-DNA-binding equilibrium by binding monomeric AtPHR1 in solution. Biochem J. 2017;474(21):3675-3687.
[51] Quintero-Troconis E, Buelvas N, Carrasco-López C, Domingo-Sananes MR, González-González L, Ramírez-Molina R, Osorio L, Lobo-Rojas A, Cáceres AJ, Michels PA, Acosta H, Quiñones W, Concepción JL. Enolase from Trypanosoma cruzi is inhibited by its interaction with metallocarboxypeptidase-1 and a putative acireductone dioxygenase. Biochim Biophys Acta Proteins Proteom. 2018 May -Jun;1866(5-6):651-660.
[52] Gerber KJ, Squires KE, Hepler JR. 14-3-3γ binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:Gα(i)-AlF(4)(-) signaling complex and RGS14 nuclear localization. J Biol Chem. 2018;293(38):14616-14631.
[53] Ham SA, Kim E, Yoo T, Lee WJ, Youn JH, Choi MJ, Han SG, Lee CH, Paek KS, Hwang JS, Seo HG. Ligand-activated interaction of PPARδ with c-Myc governs the tumorigenicity of breast cancer. Int J Cancer. 2018;143(11):2985-2996. .
[54] Ito Y, Hart JR, Vogt PK. Isoform-specific activities of the regulatory subunits of phosphatidylinositol 3-kinases - potentially novel therapeutic targets. Expert Opin Ther Targets. 2018;22(10):869-877.
[55] Novosylna A, Timchenko A, Tiktopulo E, Serdyuk I, Negrutskii B, El Skaya A. Characterization of physical properties of two isoforms of translation elongation factor 1A. Biopolym Cell. 2007; 23(5): 386-90.
[56] Timchenko AA, Novosylna OV, Prituzhalov EA, Kihara H, El'skaya AV, Negrutskii BS, Serdyuk IN. Different oligomeric properties and stability of highly homologous A1 and proto-oncogenic A2 variants of mammalian translation elongation factor eEF1. Biochemistry. 2013;52(32):5345-53.
[57] Panasyuk G, Nemazanyy I, Filonenko V, Negrutskii B, El'skaya AV. A2 isoform of mammalian translation factor eEF1A displays increased tyrosine phosphorylation and ability to interact with different signalling molecules. Int J Biochem Cell Biol. 2008;40(1):63-71.
[58] Kanibolotsky DS, Novosyl'na OV, Abbott CM, Negrutskii BS, El'skaya AV. Multiple molecular dynamics simulation of the isoforms of human translation elongation factor 1A reveals reversible fluctuations between "open" and "closed" conformations and suggests specific for eEF1A1 affinity for Ca2+-calmodulin. BMC Struct Biol. 2008;8:4.
[59] Novosylna O, Doyle A, Vlasenko D, Murphy M, Negrutskii B, El'skaya A. Comparison of the ability of mammalian eEF1A1 and its oncogenic variant eEF1A2 to interact with actin and calmodulin. Biol Chem. 2017;398(1):113-124.
[60] Andersen GR, Pedersen L, Valente L, Chatterjee I, Kinzy TG, Kjeldgaard M, Nyborg J. Structural basis for nucleotide exchange and competition with tRNA in the yeast elongation factor complex eEF1A:eEF1Balpha. Mol Cell. 2000;6(5):1261-6.
[61] Edmonds BT, Wyckoff J, Yeung YG, Wang Y, Stanley ER, Jones J, Segall J, Condeelis J. Elongation factor-1 alpha is an overexpressed actin binding protein in metastatic rat mammary adenocarcinoma. J Cell Sci. 1996;109 ( Pt 11):2705-14.
[62] Stevenson RP, Veltman D, Machesky LM. Actin-bundling proteins in cancer progression at a glance. J Cell Sci. 2012;125(Pt 5):1073-9.
[63] Peart JR, Lu R, Sadanandom A, Malcuit I, Moffett P, Brice DC, Schauser L, Jaggard DA, Xiao S, Coleman MJ, Dow M, Jones JD, Shirasu K, Baulcombe DC. Ubiquitin ligase-associated protein SGT1 is required for host and nonhost disease resistance in plants. Proc Natl Acad Sci U S A. 2002;99(16):10865-9.
[64] Komatsu K, Hashimoto M, Ozeki J, Yamaji Y, Maejima K, Senshu H, Himeno M, Okano Y, Kagiwada S, Namba S. Viral-induced systemic necrosis in plants involves both programmed cell death and the inhibition of viral multiplication, which are regulated by independent pathways. Mol Plant Microbe Interact. 2010;23(3):283-93.
[65] Li D, Wei T, Rawle DJ, Qin F, Wang R, Soares DC, Jin H, Sivakumaran H, Lin MH, Spann K, Abbott CM, Harrich D. Specific Interaction between eEF1A and HIV RT Is Critical for HIV-1 Reverse Transcription and a Potential Anti-HIV Target. PLoS Pathog. 2015;11(12):e1005289.
[66] Luan H, Shine MB, Cui X, Chen X, Ma N, Kachroo P, Zhi H, Kachroo A. The Potyviral P3 Protein Targets Eukaryotic Elongation Factor 1A to Promote the Unfolded Protein Response and Viral Pathogenesis. Plant Physiol. 2016;172(1):221-34.
[67] Rawle DJ, Li D, Swedberg JE, Wang L, Soares DC, Harrich D. HIV-1 Uncoating and Reverse Transcription Require eEF1A Binding to Surface-Exposed Acidic Residues of the Reverse Transcriptase Thumb Domain. MBio. 2018;9(2). pii: e00316-18.
[68] Novosylna O, Jurewicz E, Pydiura N, Goral A, Filipek A, Negrutskii B, El'skaya A. Translation elongation factor eEF1A1 is a novel partner of a multifunctional protein Sgt1. Biochimie. 2015;119:137-45.
[69] Li D, Wei T, Abbott CM, Harrich D. The unexpected roles of eukaryotic translation elongation factors in RNA virus replication and pathogenesis. Microbiol Mol Biol Rev. 2013;77(2):253-66.
[70] Pop C, Rouskin S, Ingolia NT, Han L, Phizicky EM, Weissman JS, Koller D. Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation. Mol Syst Biol. 2014;10:770.
[71] Tsuda-Sakurai K, Miura M. The Hidden Nature of Protein Translational Control by Diphthamide - the secrets under the leather. J Biochem. 2018 Sep 11.
[72] Futernyk P, Pogribna A, Petrushenko Z, Negrutski B, El'skaya G. Investigation of the complexes of elongation factor 1A with tRNASer and seryl-tRNA synthetase. Biopolym Cell. 2004; 20(1-2): 17-23.
[73] Futernyk P, Negrutskii B, El’ska G. Noncanonical complexes of mammalian eEF1A with various deacylated tRNAs. Biopolym Cell. 2008; 24(6): 453-62.
[74] Futernyk P, Negrutskii B, El’skaya A. Interaction of different tRNAs with translation elongation factors 1A from lower and higher eukaryotes. Biopolym Cell. 2009; 25(6): 457-65.
[75] Pape T, Wintermeyer W, Rodnina MV. Complete kinetic mechanism of elongation factor Tu-dependent binding of aminoacyl-tRNA to the A site of the E. coli ribosome. EMBO J. 1998;17(24):7490-7.
[76] Bonven B, Gulløv K. Peptide chain elongation rate and ribosomal activity in Saccharomyces cerevisiae as a function of the growth rate. Mol Gen Genet. 1979;170(2):225-30.
[77] Bouadloun F, Donner D, Kurland CG. Codon-specific missense errors in vivo. EMBO J. 1983;2(8):1351-6.
[78] Negrutskii B, Vlasenko D, Mirande M, Futernyk P, El'skaya A. mRNA-Independent way to regulate translation elongation rate in eukaryotic cells. IUBMB Life. 2018;70(3):192-196.
[79] Newbery HJ, Loh DH, O'Donoghue JE, Tomlinson VA, Chau YY, Boyd JA, Bergmann JH, Brownstein D, Abbott CM. Translation elongation factor eEF1A2 is essential for post-weaning survival in mice. J Biol Chem. 2007;282(39):28951-9.
[80] Takei N, Kawamura M, Ishizuka Y, Kakiya N, Inamura N, Namba H, Nawa H. Brain-derived neurotrophic factor enhances the basal rate of protein synthesis by increasing active eukaryotic elongation factor 2 levels and promoting translation elongation in cortical neurons. J Biol Chem. 2009;284(39):26340-8. PubMed Central
[81] Barrera I, Flores-Méndez M, Hernández-Kelly LC, Cid L, Huerta M, Zinker S, López-Bayghen E, Aguilera J, Ortega A. Glutamate regulates eEF1A phosphorylation and ribosomal transit time in Bergmann glial cells. Neurochem Int. 2010Dec;57(7):795-803.
[82] Murugan A, Huse DA, Leibler S. Speed, dissipation, and error in kinetic proofreading. Proc Natl Acad Sci U S A. 2012;109(30):12034-9.
[83] Cochella L, Green R. Fidelity in protein synthesis. Curr Biol. 2005;15(14):R536-40.
[84] Belin S, Beghin A, Solano-Gonzàlez E, Bezin L, Brunet-Manquat S, Textoris J, Prats AC, Mertani HC, Dumontet C, Diaz JJ. Dysregulation of ribosome biogenesis and translational capacity is associated with tumor progression of human breast cancer cells. PLoS One. 2009;4(9):e7147.
[85] Liu Y, Song C, Ni H, Jiao W, Gan W, Dong X, Liu J, Zhu L, Zhai X, Hu Z, Li J. UBE2L3, a susceptibility gene that plays oncogenic role in hepatitis B-related hepatocellular carcinoma. J Viral Hepat. 2018;25(11):1363-1371.
[86] Darvishian M, Janjua NZ, Chong M, Cook D, Samji H, Butt ZA, Yu A, Alvarez M, Yoshida E, Ramji A, Wong J, Woods R, Tyndall M, Krajden M. Estimating the impact of early hepatitis C virus clearance on hepatocellular carcinoma risk. J Viral Hepat. 2018;25(12):1481-1492.
[87] Ye C, Zhang C, Huang H, Yang B, Xiao G, Kong D, Tian Q, Song Q, Song Y, Tan H, Wang Y, Zhou T, Zi X, Sun Y. The Natural Compound Myricetin Effectively Represses the Malignant Progression of Prostate Cancer by Inhibiting PIM1 and Disrupting the PIM1/CXCR4 Interaction. Cell Physiol Biochem. 2018;48(3):1230-1244.