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Leslie Parent

TitleProfessor
InstitutionCollege of Medicine
DepartmentMedicine
Address500 University Drive Hershey PA 17033
Phone7175318881

 Overview 
 overview
PREFERRED TITLE/ROLE:



Physician, Professor of Medicine, Co-Director of the MD/PhD Program, Co-Leader of the Penn State CTSI Pilot and Collaborative Translational and Clinical Studies



SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):



Department of Microbiology and Immunology; Penn State Cancer Institute; Clinical and Translational Studies Institute; Graduate Faculty; Biomedical Sciences Faculty



GRADUATE PROGRAM AFFILIATIONS:



Biomedical Sciences, Cell and Molecular Biology, MD/PhD Degree Program, Microbiology and Immunology, Genetics



EDUCATION:



M.D., Duke University School of Medicine, 1987

Residency in Internal Medicine, Duke University Medical Center, 1989-1991

Fellowship in Infectious Diseases, Penn State College of Medicine, 1991-1994

Postdoctoral Training in Retrovirology, Penn State College of Medicine, 1992-1997



NARRATIVE:



Retrovirus-Cell Interactions



Overall goals: Our research centers around understanding the interactions between viruses and host cells at the molecular level. We use retroviruses as a model system to dissect molecular mechanisms of virus replication, which has led us to study the intracellular trafficking pathways of retroviral proteins and cellular factors that are recruited to facilitate virus propagation.



Retrovirus replication: The main structural proteins of the oncogenic retrovirus Rous sarcoma virus (RSV) are the Gag proteins, which are initially synthesized as a polyprotein precursor. The Gag polyprotein directs the assembly and budding of progeny retrovirus particles from the plasma membrane of infected cells. Gag proteins are synthesized on free ribosomes in the cytosol, and previously it was believed that they were then targeted directly to the plasma membrane. However, we discovered that the RSV Gag protein enters the nucleus using signals in the MA and NC domains for nuclear targeting. Gag proteins are exported out of the nucleus through the nuclear pore complex via the cellular exportin CRM-1 pathway and an interaction with the nuclear pore complex proteins Nup98 and Nup214. After nuclear export, Gag proteins form multimeric complexes bound to viral RNA. The assembling virus particles are targeted to the plasma membrane where they interact with cellular machinery to allow budding of nascent virions.



One of our main goals is to understand what role Gag proteins play in the nucleus. Collectively, our data suggest that the RSV Gag polyprotein enters the nucleus to interact with the unspliced viral RNA to initiate the genome encapsidation process. Our data support a model in which (i) Gag binds as a monomer to nuclear import factors (importin-11, transportin-SR, and importin alpha/beta) for nuclear entry, (ii) Gag binds to the viral genome in the nucleus, oligomerizes, and undergoes a conformational change that exposes its nuclear export signal in the p10 domain to facilitate binding of CRM1/RanGTP, (iii) Gag-viral RNA complexes are exported from the nucleus and traffic to the plasma membrane using host transport factors. This model represents a novel paradigm for how retroviruses select and package their genomes.



We use genetic, biochemical, biophysical, and dynamic live cell imaging approaches to dissect the mechanisms that control the trafficking of retroviruses in infected cells. By identifying the signals and host factors involved in transport of retroviral proteins and RNAs through different subcellular compartments, our research interfaces with basic questions in cellular biology.


 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Stake MS, Bann DV, Kaddis RJ, Parent LJ. Nuclear trafficking of retroviral RNAs and Gag proteins during late steps of replication. Viruses. 2013 Nov; 5(11):2767-95.
    View in: PubMed
  2. Webb JA, Jones CP, Parent LJ, Rouzina I, Musier-Forsyth K. Distinct binding interactions of HIV-1 Gag to Psi and non-Psi RNAs: implications for viral genomic RNA packaging. RNA. 2013 Aug; 19(8):1078-88.
    View in: PubMed
  3. Nadaraia-Hoke S, Bann DV, Lochmann TL, Gudleski-O'Regan N, Parent LJ. Alterations in the MA and NC domains modulate phosphoinositide-dependent plasma membrane localization of the Rous sarcoma virus Gag protein. J Virol. 2013 Mar; 87(6):3609-15.
    View in: PubMed
  4. Beyer AR, Bann DV, Rice B, Pultz IS, Kane M, Goff SP, Golovkina TV, Parent LJ. Nucleolar trafficking of the mouse mammary tumor virus gag protein induced by interaction with ribosomal protein L9. J Virol. 2013 Jan; 87(2):1069-82.
    View in: PubMed
  5. Lochmann TL, Bann DV, Ryan EP, Beyer AR, Mao A, Cochrane A, Parent LJ. NC-mediated nucleolar localization of retroviral gag proteins. Virus Res. 2013 Feb; 171(2):304-18.
    View in: PubMed
  6. Bann DV, Parent LJ. Application of live-cell RNA imaging techniques to the study of retroviral RNA trafficking. Viruses. 2012 Jun; 4(6):963-79.
    View in: PubMed
  7. Parent LJ, Gudleski N. Beyond plasma membrane targeting: role of the MA domain of Gag in retroviral genome encapsidation. J Mol Biol. 2011 Jul 22; 410(4):553-64.
    View in: PubMed
  8. Parent LJ. New insights into the nuclear localization of retroviral Gag proteins. Nucleus. 2011 Mar-Apr; 2(2):92-7.
    View in: PubMed
  9. Gudleski N, Flanagan JM, Ryan EP, Bewley MC, Parent LJ. Directionality of nucleocytoplasmic transport of the retroviral gag protein depends on sequential binding of karyopherins and viral RNA. Proc Natl Acad Sci U S A. 2010 May 18; 107(20):9358-63.
    View in: PubMed
  10. Garbitt-Hirst R, Kenney SP, Parent LJ. Genetic evidence for a connection between Rous sarcoma virus gag nuclear trafficking and genomic RNA packaging. J Virol. 2009 Jul; 83(13):6790-7.
    View in: PubMed
  11. Kenney SP, Lochmann TL, Schmid CL, Parent LJ. Intermolecular interactions between retroviral Gag proteins in the nucleus. J Virol. 2008 Jan; 82(2):683-91.
    View in: PubMed
  12. Scheifele LZ, Kenney SP, Cairns TM, Craven RC, Parent LJ. Overlapping roles of the Rous sarcoma virus Gag p10 domain in nuclear export and virion core morphology. J Virol. 2007 Oct; 81(19):10718-28.
    View in: PubMed
  13. Julian K, Kosowska-Shick K, Whitener C, Roos M, Labischinski H, Rubio A, Parent L, Ednie L, Koeth L, Bogdanovich T, Appelbaum PC. Characterization of a daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus strain in a patient with endocarditis. Antimicrob Agents Chemother. 2007 Sep; 51(9):3445-8.
    View in: PubMed
  14. Butterfield-Gerson KL, Scheifele LZ, Ryan EP, Hopper AK, Parent LJ. Importin-beta family members mediate alpharetrovirus gag nuclear entry via interactions with matrix and nucleocapsid. J Virol. 2006 Feb; 80(4):1798-806.
    View in: PubMed
  15. Scheifele LZ, Ryan EP, Parent LJ. Detailed mapping of the nuclear export signal in the Rous sarcoma virus Gag protein. J Virol. 2005 Jul; 79(14):8732-41.
    View in: PubMed
  16. Julian KG, de Flesco L, Clarke LE, Parent LJ. Actinomyces viscosus endocarditis requiring aortic valve replacement. J Infect. 2005 May; 50(4):359-62.
    View in: PubMed
  17. Garbitt RA, Bone KR, Parent LJ. Insertion of a classical nuclear import signal into the matrix domain of the Rous sarcoma virus Gag protein interferes with virus replication. J Virol. 2004 Dec; 78(24):13534-42.
    View in: PubMed
  18. Whitener CJ, Park SY, Browne FA, Parent LJ, Julian K, Bozdogan B, Appelbaum PC, Chaitram J, Weigel LM, Jernigan J, McDougal LK, Tenover FC, Fridkin SK. Vancomycin-resistant Staphylococcus aureus in the absence of vancomycin exposure. Clin Infect Dis. 2004 Apr 15; 38(8):1049-55.
    View in: PubMed
  19. Scheifele LZ, Rhoads JD, Parent LJ. Specificity of plasma membrane targeting by the rous sarcoma virus gag protein. J Virol. 2003 Jan; 77(1):470-80.
    View in: PubMed
  20. Scheifele LZ, Garbitt RA, Rhoads JD, Parent LJ. Nuclear entry and CRM1-dependent nuclear export of the Rous sarcoma virus Gag polyprotein. Proc Natl Acad Sci U S A. 2002 Mar 19; 99(6):3944-9.
    View in: PubMed
  21. Garbitt RA, Albert JA, Kessler MD, Parent LJ. trans-acting inhibition of genomic RNA dimerization by Rous sarcoma virus matrix mutants. J Virol. 2001 Jan; 75(1):260-8.
    View in: PubMed
  22. Berrou L, Bernatchez G, Parent L. Molecular determinants of inactivation within the I-II linker of alpha1E (CaV2.3) calcium channels. Biophys J. 2001 Jan; 80(1):215-28.
    View in: PubMed
  23. Parent LJ, Cairns TM, Albert JA, Wilson CB, Wills JW, Craven RC. RNA dimerization defect in a Rous sarcoma virus matrix mutant. J Virol. 2000 Jan; 74(1):164-72.
    View in: PubMed
  24. Garnier L, Parent LJ, Rovinski B, Cao SX, Wills JW. Identification of retroviral late domains as determinants of particle size. J Virol. 1999 Mar; 73(3):2309-20.
    View in: PubMed
  25. Puffer BA, Parent LJ, Wills JW, Montelaro RC. Equine infectious anemia virus utilizes a YXXL motif within the late assembly domain of the Gag p9 protein. J Virol. 1997 Sep; 71(9):6541-6.
    View in: PubMed
  26. Parent LJ, Wilson CB, Resh MD, Wills JW. Evidence for a second function of the MA sequence in the Rous sarcoma virus Gag protein. J Virol. 1996 Feb; 70(2):1016-26.
    View in: PubMed
  27. Craven RC, Parent LJ. Dynamic interactions of the Gag polyprotein. Curr Top Microbiol Immunol. 1996; 214:65-94.
    View in: PubMed
  28. Parent LJ, Salam MM, Appelbaum PC, Dossett JH. Disseminated Mycobacterium marinum infection and bacteremia in a child with severe combined immunodeficiency. Clin Infect Dis. 1995 Nov; 21(5):1325-7.
    View in: PubMed
  29. Parent L, Gopalakrishnan M. Glutamate substitution in repeat IV alters divalent and monovalent cation permeation in the heart Ca2+ channel. Biophys J. 1995 Nov; 69(5):1801-13.
    View in: PubMed
  30. Goldsmith MA, Lai SY, Xu W, Amaral MC, Kuczek ES, Parent LJ, Mills GB, Tarr KL, Longmore GD, Greene WC. Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the beta chain and non-tyrosine residues of the gamma c chain. J Biol Chem. 1995 Sep 15; 270(37):21729-37.
    View in: PubMed
  31. Parent LJ, Bennett RP, Craven RC, Nelle TD, Krishna NK, Bowzard JB, Wilson CB, Puffer BA, Montelaro RC, Wills JW. Positionally independent and exchangeable late budding functions of the Rous sarcoma virus and human immunodeficiency virus Gag proteins. J Virol. 1995 Sep; 69(9):5455-60.
    View in: PubMed
  32. Zhou W, Parent LJ, Wills JW, Resh MD. Identification of a membrane-binding domain within the amino-terminal region of human immunodeficiency virus type 1 Gag protein which interacts with acidic phospholipids. J Virol. 1994 Apr; 68(4):2556-69.
    View in: PubMed
  33. Singer DS, Parent LJ, Kolber MA. Ethanol: an enhancer of transplantation antigen expression. Alcohol Clin Exp Res. 1989 Aug; 13(4):480-4.
    View in: PubMed
  34. Sonies BC, Parent LJ, Morrish K, Baum BJ. Durational aspects of the oral-pharyngeal phase of swallow in normal adults. Dysphagia. 1988; 3(1):1-10.
    View in: PubMed
  35. Parent LJ, Ehrlich R, Matis L, Singer DS. Ethanol: an enhancer of major histocompatibility complex antigen expression. FASEB J. 1987 Dec; 1(6):469-73.
    View in: PubMed
  36. Singer DS, Parent LJ, Ehrlich R. Identification and DNA sequence of an interspersed repetitive DNA element in the genome of the miniature swine. Nucleic Acids Res. 1987 Mar 25; 15(6):2780.
    View in: PubMed
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