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Shawn Murphy

TitleAssociate Professor
InstitutionSchool of Medicine and Dentistry
DepartmentObstetrics and Gynecology
AddressUniversity of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 668
Rochester NY 14642
Other Positions
TitleAssociate Professor
InstitutionSchool of Medicine and Dentistry
DepartmentMicrobiology and Immunology

 
 Awards And Honors
1984     Best Student Poster Presentation, 17th Annual Southeastern Development Biology Conference, Columbia, SC
1999     Olympus Award for New Investigators, European Placenta Group Meeting, Schladming, Austria
2002     Semi-finalist, Western New York Inventor of the Year
2006     1st Annual Human Placenta Workshop Lecturer
2007     2nd Annual Human Placenta Workshop Lecturer
2008     3rd Annual Human Placenta Workshop Lecturer
2008     Guest editor, special edition of Immunological Investigations on Reproductive Immunology
 
 Overview
One of the long term goals of our research is to determine why the maternal immune system does not reject the genetically disparate fetus during pregnancy. Our studies are focused primarily on the immunoregulatory properties of trophoblast cells, which are the first cells to differentiate from the embryo, and ultimately form the fetal component of the placenta. Trophoblast cells are the only cells derived from the blastocyst that are in direct contact with maternal blood, and therefore play an essential role in protecting the fetus from attack from the maternal immune system. Trophoblast cells are relatively unique in that they do not express major histocompatibility complex (MHC) class II antigens, either constitutively, or after exposure to IFN-gamma. The absence of MHC class II antigen expression on trophoblast cells is thought to be critical for prevention of deleterious maternal immune responses against the fetus. Thus, successful reproduction of mammals may require that MHC class II gene expression be stringently repressed in trophoblast cells. We previously demonstrated that the inability of human and rodent trophoblast cells to transcribe MHC class II genes following IFN-gamma treatment results from silencing of expression of the class II transactivator (CIITA), a transacting transcription factor essential for constitutive and IFN-gamma-inducible transcription in other cell types. We have therefore been investigating the molecular mechanisms underlying transcriptional silencing of CIITA in trophoblast cells. Our studies to date suggest that silencing of CIITA expression in trophoblast cells exposed to IFN-gamma is due to at least two overlapping mechanisms: 1) hyporesponsiveness to IFN-gamma, and 2) a repressive chromatin structure at the CIITA promoter.

Our recent studies demonstrated that responses of both human and mouse trophoblast cells to IFN-gamma are significantly reduced relative to other cell types, which correspond with both the inability to express MHC class II molecules, and resistance of trophoblast cells to IFN-gamma-mediated apoptosis and inhibition of cell proliferation. Based on the fact that a wide range of pathogens, including multiple viruses, bacteria and mycobacteria have evolved mechanisms for inhibiting cellular responses to IFN-gamma as an important mechanism of immunoevasion, we have proposed that trophoblastic suppression of IFN-gamma signaling is essential for successful pregnancy. Thus, we have been investigating how trophoblast cells inhibit IFN-gamma signaling.

Our laboratory is also examining the mechanisms accounting for loss of MHC class II antigen expression in human diffuse large B cell lymphoma (DLBLCL). Downregulation of MHC class II expression on DLBLCL is associated with significant decreases in patient survival. Our recent studies in collaboration with Dr. Lisa Rimsza's group demonstrate that the most common mechanism underlying MHC class II loss in DLBCL is silencing of CIITA expression. Thus, we are currently examining the molecular mechanisms responsible for silencing CIITA in DLBCL.

 
 Selected Publications
List All   |   Timeline
  1. Lim JY, Gerber SA, Murphy SP, Lord EM. Type I interferons induced by radiation therapy mediate recruitment and effector function of CD8(+) T cells. Cancer Immunol Immunother. 2014 Mar; 63(3):259-71.
    View in: PubMed
  2. Gerber SA, Lim JY, Connolly KA, Sedlacek AL, Barlow ML, Murphy SP, Egilmez NK, Lord EM. Radio-responsive tumors exhibit greater intratumoral immune activity than nonresponsive tumors. Int J Cancer. 2014 May 15; 134(10):2383-92.
    View in: PubMed
  3. Cycon KA, Mulvaney K, Rimsza LM, Persky D, Murphy SP. Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma. Immunology. 2013 Oct; 140(2):259-72.
    View in: PubMed
  4. Gerber SA, Sedlacek AL, Cron KR, Murphy SP, Frelinger JG, Lord EM. IFN-? Mediates the Antitumor Effects of Radiation Therapy in a Murine Colon Tumor. Am J Pathol. 2013 Jun; 182(6):2345-54.
    View in: PubMed
  5. Katzman PJ, Murphy SP, Oble DA. Immunohistochemical analysis reveals an influx of regulatory T cells and focal trophoblastic STAT-1 phosphorylation in chronic villitis of unknown etiology. Pediatr Dev Pathol. 2011 Jul-Aug; 14(4):284-93.
    View in: PubMed
  6. Bushway M, Cycon KA, Mulvaney K, Murphy SP. Coordinate loss of MHC class II expression in the diffuse large B cell lymphoma cell line OCI-Ly2 is due to a novel mutation in RFX-AP. Immunogenetics. 2010 Feb; 62(2):109-16.
    View in: PubMed
  7. Wilkinson ST, Fernandez DR, Murphy SP, Braziel RM, Campo E, Chan WC, Delabie J, Gascoyne RD, Staudt LM, Jaffe ES, Rosenwald A, Rimsza LM. Decreased major histocompatibility complex class II expression in diffuse large B-cell lymphoma does not correlate with CpG methylation of class II transactivator promoters III and IV. Leuk Lymphoma. 2009 Nov; 50(11):1875-8.
    View in: PubMed
  8. Choi JC, Holtz R, Murphy SP. Histone deacetylases inhibit IFN-gamma-inducible gene expression in mouse trophoblast cells. J Immunol. 2009 May 15; 182(10):6307-15.
    View in: PubMed
  9. Apps R, Murphy SP, Fernando R, Gardner L, Ahad T, Moffett A. Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies. Immunology. 2009 May; 127(1):26-39.
    View in: PubMed
  10. Rimsza LM, Chan WC, Gascoyne RD, Campo E, Jaffe ES, Staudt LM, Delabie J, Rosenwald A, Murphy SP. CIITA or RFX coding region loss of function mutations occur rarely in diffuse large B-cell lymphoma cases and cell lines with low levels of major histocompatibility complex class II expression. Haematologica. 2009 Apr; 94(4):596-8.
    View in: PubMed
  11. Murphy SP, Tayade C, Ashkar AA, Hatta K, Zhang J, Croy BA. Interferon gamma in successful pregnancies. Biol Reprod. 2009 May; 80(5):848-59.
    View in: PubMed
  12. Cycon KA, Clements JL, Holtz R, Fuji H, Murphy SP. The immunogenicity of L1210 lymphoma clones correlates with their ability to function as antigen-presenting cells. Immunology. 2009 Sep; 128(1 Suppl):e641-51.
    View in: PubMed
  13. Cycon KA, Rimsza LM, Murphy SP. Alterations in CIITA constitute a common mechanism accounting for downregulation of MHC class II expression in diffuse large B-cell lymphoma (DLBCL). Exp Hematol. 2009 Feb; 37(2):184-194.
    View in: PubMed
  14. Croy BA, Murphy SP. Maternal-fetal immunology. Immunol Invest. 2008; 37(5):389-94.
    View in: PubMed
  15. Choi JC, Holtz R, Petroff MG, Alfaidy N, Murphy SP. Dampening of IFN-gamma-inducible gene expression in human choriocarcinoma cells is due to phosphatase-mediated inhibition of the JAK/STAT-1 pathway. J Immunol. 2007 Feb 1; 178(3):1598-607.
    View in: PubMed
  16. Murphy SP, Choi JC, Holtz R. Regulation of major histocompatibility complex class II gene expression in trophoblast cells. Reprod Biol Endocrinol. 2004 Jul 5; 2:52.
    View in: PubMed
  17. Chang CC, Murphy SP, Ferrone S. Differential in vivo and in vitro HLA-G expression in melanoma cells: potential mechanisms. Hum Immunol. 2003 Nov; 64(11):1057-63.
    View in: PubMed
  18. Holtz R, Choi JC, Petroff MG, Piskurich JF, Murphy SP. Class II transactivator (CIITA) promoter methylation does not correlate with silencing of CIITA transcription in trophoblasts. Biol Reprod. 2003 Sep; 69(3):915-24.
    View in: PubMed
  19. Murphy SP, Holtz R, Lewandowski N, Tomasi TB, Fuji H. DNA alkylating agents alleviate silencing of class II transactivator gene expression in L1210 lymphoma cells. J Immunol. 2002 Sep 15; 169(6):3085-93.
    View in: PubMed
  20. Li LH, Sen A, Murphy SP, Jahreis GP, Fuji H, Hui SW. Apoptosis induced by DNA uptake limits transfection efficiency. Exp Cell Res. 1999 Dec 15; 253(2):541-50.
    View in: PubMed
  21. Murphy SP, Tomasi TB. Absence of MHC class II antigen expression in trophoblast cells results from a lack of class II transactivator (CIITA) gene expression. Mol Reprod Dev. 1998 Sep; 51(1):1-12.
    View in: PubMed
  22. Murphy SP, Gollnick SO, Pazmany T, Maier P, Elkin G, Tomasi TB. Repression of MHC class II gene transcription in trophoblast cells by novel single-stranded DNA binding proteins. Mol Reprod Dev. 1997 Aug; 47(4):390-403.
    View in: PubMed
  23. Pazmany T, Murphy SP, Gollnick SO, Brooks SP, Tomasi TB. Activation of multiple transcription factors and fos and jun gene family expression in cells exposed to a single electric pulse. Exp Cell Res. 1995 Nov; 221(1):103-10.
    View in: PubMed
  24. Bhattacharyya T, Karnezis AN, Murphy SP, Hoang T, Freeman BC, Phillips B, Morimoto RI. Cloning and subcellular localization of human mitochondrial hsp70. J Biol Chem. 1995 Jan 27; 270(4):1705-10.
    View in: PubMed
  25. Mathur SK, Sistonen L, Brown IR, Murphy SP, Sarge KD, Morimoto RI. Deficient induction of human hsp70 heat shock gene transcription in Y79 retinoblastoma cells despite activation of heat shock factor 1. Proc Natl Acad Sci U S A. 1994 Aug 30; 91(18):8695-9.
    View in: PubMed
  26. Murphy SP, Gorzowski JJ, Sarge KD, Phillips B. Characterization of constitutive HSF2 DNA-binding activity in mouse embryonal carcinoma cells. Mol Cell Biol. 1994 Aug; 14(8):5309-17.
    View in: PubMed
  27. Abravaya K, Myers MP, Murphy SP, Morimoto RI. The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression. Genes Dev. 1992 Jul; 6(7):1153-64.
    View in: PubMed
  28. Murphy SP, Garbern J, Odenwald WF, Lazzarini RA, Linney E. Differential expression of the homeobox gene Hox-1.3 in F9 embryonal carcinoma cells. Proc Natl Acad Sci U S A. 1988 Aug; 85(15):5587-91.
    View in: PubMed

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