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Martyn K. White, PhDMartyn K. White, PhD

 

Assistant Professor, Neuroscience

Assistant Professor, Neurovirology

Location: Room 756 MERB

Telephone:  215-707-8309

Fax:  215-707-4888

Email: whitem@temple.edu

 

Department of Neuroscience

Center for Neurovirology

 

Educational Background:

 

BA, Biochemistry - 1979

University of Oxford

United Kingdom

 

MS, Biochemistry - 1982

University of Oxford

United Kingdom

 

DPhil, Cell Biology - 1983
University of Oxford
United Kingdom

 

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Research Interests:

 

Studies of the molecular mechanisms that are involved in the reactivation of JC virus: role of cytokines and transcription factors.


Research Summary


Our research is focused on advancing understanding of the human neurotropic polyomavirus JC, also known as JC virus (JCV), which replicates in the glial cells of the brain to cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease for which there is no effective therapy. Remarkably, while PML is very rare, JCV infection is very common in the population and serological studies indicate that most people have been exposed to the virus. Although the life cycle is still poorly understood, infection is thought to occur asymptomatically during childhood and the virus then enters a latent or persistent state. PML occurs when JCV reactivates from latency in the brain and destroys the myelin-producing oligodendrocytes. The common feature of nearly all cases of PML is an underlying impairment of cellular immune function, e.g., HIV/AIDS or treatment with new immunomodulatory monoclonal antibody therapies such as Natalizumab.


The aim of our research is to understand the molecular mechanisms of JCV reactivation from latency to cause PML. It has become clear from studies conducted in many independent laboratories that viral DNA, but not cell protein, is present in cells of the CNS from some normal individuals without PML, i.e., glial cells in the brain represent a site for viral latency. We have discovered that the JCV non-coding control region (NCCR), which regulates viral transcription and replication, contains a number of DNA elements that may determine whether the virus is in an active or inactive state. These elements cause activation by binding transcription factors, e.g., NF-kappaB, C/EBPbeta and Egr-1 that are regulated by extracellular cytokines. This has led us to test the hypothesis that alterations in cytokine profiles that are associated with immunosuppressive states may play a role in the reactivation of JCV from latency of the CNS that occurs under conditions of immunosuppression particularly in the context of HIV-1/AIDS. For example, we have developed a variety of wild-type and mutant transcription reporter constructs and have shown that the proinflammatory cytokine TNF-alpha stimulated both early and late JCV transcription in both astrocytic and oligodendroglial cells. Indeed a defined DNA segment from the JCV NCCR was able to confer TNF-alpha responsiveness to a heterologous promoter. Further, immunohistochemistry of HIV+/PML patient lesions revealed robust labeling for TNF-alpha and TNFR-1.


In our current research, we are continuing to examine the molecular details of interactions of cellular transcription factors with regulatory elements in the JCV NCCR and the impact of the activation of cellular signaling pathways and have begun to examine the role of epigenetic modifications in the regulation of JCV activation. Better understanding of the molecular events leading to JCV reactivation and the onset of PML may allow the development of new therapeutic modalities.

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PUBMED PUBLICATIONS :


Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

24672035. Coric P, Sami Saribas A, Abou-Gharbia M, Childers W, White MK, Bouaziz S, Safak M, Nuclear magnetic resonance structure revealed that human polyoma JC virus agnoprotein contains an alpha-helix encompassing the Leu/Ile/Phe-rich domain. J Virol :()2014 Mar 26

24648009. Wang JY, Darbinyan A, White MK, Darbinian N, Reiss K, Amini S, Involvement of IRS-1 Interaction with ADAM10 in the Regulation of Neurite Extension. J Cell Physiol :()2013 Dec 16

24418532. Saribas AS, Mun S, Johnson J, El-Hajmoussa M, White MK, Safak M, Human polyoma JC virus minor capsid proteins, VP2 and VP3, enhance large T antigen binding to the origin of viral DNA replication: evidence for their involvement in regulation of the viral DNA replication. Virology 449:(1-16)2014 Jan 20

24277482. Pozniak PD, White MK, Khalili K, TNF-a/NF-?B Signaling in the CNS: Possible Connection to EPHB2. J Neuroimmune Pharmacol 9:2(133-41)2014 Mar

23975827. Wollebo HS, Woldemichaele B, White MK, Lentiviral transduction of neuronal cells. Methods Mol Biol 1078:(141-6)2013

23975816. Gordon J, Amini S, White MK, General overview of neuronal cell culture. Methods Mol Biol 1078:(1-8)2013

23971673. Wollebo HS, Woldemichaele B, Khalili K, Safak M, White MK, Epigenetic regulation of polyomavirus JC. Virol J 10:(264)2013 Aug 23

23747198. Sami Saribas A, Abou-Gharbia M, Childers W, Sariyer IK, White MK, Safak M, Essential roles of Leu/Ile/Phe-rich domain of JC virus agnoprotein in dimer/oligomer formation, protein stability and splicing of viral transcripts. Virology 443:1(161-76)2013 Aug 15

23516356. White MK, Gordon J, Khalili K, The rapidly expanding family of human polyomaviruses: recent developments in understanding their life cycle and role in human pathology. PLoS Pathog 9:3(e1003206)2013 Mar

23086711. Darbinyan A, Kaminski R, White MK, Darbinian-Sarkissian N, Khalili K, Polyomavirus JC infection inhibits differentiation of oligodendrocyte progenitor cells. J Neurosci Res 91:1(116-27)2013 Jan

22840425. Saribas AS, White MK, Safak M, JC virus agnoprotein enhances large T antigen binding to the origin of viral DNA replication: evidence for its involvement in viral DNA replication. Virology 433:1(12-26)2012 Nov 10

22749879. Wollebo HS, Melis S, Khalili K, Safak M, White MK, Cooperative roles of NF-?B and NFAT4 in polyomavirus JC regulation at the KB control element. Virology 432:1(146-54)2012 Oct 10

21936015. Tavazzi E, White MK, Khalili K, Progressive multifocal leukoencephalopathy: clinical and molecular aspects. Rev Med Virol 22:1(18-32)2012 Jan

21920573. Saribas AS, Arachea BT, White MK, Viola RE, Safak M, Human polyomavirus JC small regulatory agnoprotein forms highly stable dimers and oligomers: implications for their roles in agnoprotein function. Virology 420:1(51-65)2011 Nov 10

21609431. Sariyer IK, Saribas AS, White MK, Safak M, Infection by agnoprotein-negative mutants of polyomavirus JC and SV40 results in the release of virions that are mostly deficient in DNA content. Virol J 8:(255)2011 May 24

21311094. White MK, Khalili K, Could NSP5a3a be a target for head and neck cancer? Oncotarget 1:6(386)2010 Oct

21227915. White MK, Khalili K, Pathogenesis of progressive multifocal leukoencephalopathy--revisited. J Infect Dis 203:5(578-86)2011 Mar 1

21185609. Wollebo HS, Safak M, Del Valle L, Khalili K, White MK, Role for tumor necrosis factor-a in JC virus reactivation and progressive multifocal leukoencephalopathy. J Neuroimmunol 233:1-2(46-53)2011 Apr

21117063. Darbinian N, Gomberg R, Mullen L, Garcia S, White MK, Khalili K, Amini S, Suppression of HIV-1 transcriptional elongation by a DING phosphatase. J Cell Biochem 112:1(225-32)2011 Jan

20948313. Kaminski R, Cheeseboro L, Amini S, Johnson EM, White MK, Khalili K, Darbinyan A, Role of Pura in the cellular response to ultraviolet-C radiation. Cell Cycle 9:20(4164-73)2010 Oct 15

20890127. Rom I, Darbinyan A, White MK, Rappaport J, Sawaya BE, Amini S, Khalili K, Activation of HIV-1 LTR by Rad51 in microglial cells. Cell Cycle 9:18(3715-22)2010 Sep 15

20554301. Tremolada S, Akan S, Otte J, Khalili K, Ferrante P, Chaudhury PR, Woodle ES, Trofe-Clark J, White MK, Gordon J, Rare subtypes of BK virus are viable and frequently detected in renal transplant recipients with BK virus-associated nephropathy. Virology 404:2(312-8)2010 Sep 1

19747512. Romagnoli L, Wollebo HS, Deshmane SL, Mukerjee R, Del Valle L, Safak M, Khalili K, White MK, Modulation of JC virus transcription by C/EBPbeta. Virus Res 146:1-2(97-106)2009 Dec

19640999. White MK, Safak M, Khalili K, Regulation of gene expression in primate polyomaviruses. J Virol 83:21(10846-56)2009 Nov

19282432. Basile A, Darbinian N, Kaminski R, White MK, Gentilella A, Turco MC, Khalili K, Evidence for modulation of BAG3 by polyomavirus JC early protein. J Gen Virol 90:Pt 7(1629-40)2009 Jul

19182532. White MK, Johnson EM, Khalili K, Multiple roles for Puralpha in cellular and viral regulation. Cell Cycle 8:3(1-7)2009 Feb 1

18927497. Kaminski R, Darbinyan A, Merabova N, Deshmane SL, White MK, Khalili K, Protective role of Puralpha to cisplatin. Cancer Biol Ther 7:12(1926-35)2008 Dec

18719392. Mukerjee R, Deshmane SL, Fan S, Del Valle L, White MK, Khalili K, Amini S, Sawaya BE, Involvement of the p53 and p73 transcription factors in neuroAIDS. Cell Cycle 7:17(2682-90)2008 Sep 1

18648329. Del Valle L, White MK, Khalili K, Potential mechanisms of the human polyomavirus JC in neural oncogenesis. J Neuropathol Exp Neurol 67:8(729-40)2008 Aug

18630497. Wang H, White MK, Kaminski R, Darbinian N, Amini S, Johnson EM, Khalili K, Rappaport J, Role of Puralpha in the modulation of homologous recombination-directed DNA repair by HIV-1 Tat. Anticancer Res 28:3A(1441-7)2008 May-Jun

18379198. White MK, Amini S, Khalili K, Kogan M, Donaldson K, Darbinian N, Development of a bidirectional caspase-3 expression system for the induction of apoptosis. Cancer Biol Ther 7:6(945-54)2008 Jun

18353421. Romagnoli L, Sariyer IK, Tung J, Feliciano M, Sawaya BE, Del Valle L, Ferrante P, Khalili K, Safak M, White MK, Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter. Virology 375:2(331-41)2008 Jun 5

17989177. Merabova N, Kaniowska D, Kaminski R, Deshmane SL, White MK, Amini S, Darbinyan A, Khalili K, JC virus agnoprotein inhibits in vitro differentiation of oligodendrocytes and promotes apoptosis. J Virol 82:3(1558-69)2008 Feb

17389301. Khalili K, White MK, Lublin F, Ferrante P, Berger JR, Reactivation of JC virus and development of PML in patients with multiple sclerosis. Neurology 68:13(985-90)2007 Mar 27

17368705. Darbinyan A, White MK, Akan S, Radhakrishnan S, Del Valle L, Amini S, Khalili K, Alterations of DNA damage repair pathways resulting from JCV infection. Virology 364:1(73-86)2007 Jul 20

17201119. White MK, Skowronska A, Gordon J, Del Valle L, Deshmane SL, Giordano A, Khalili K, Analysis of a mutant p53 protein arising in a medulloblastoma from a mouse transgenic for the JC virus early region. Anticancer Res 26:6B(4079-92)2006 Nov-Dec

16936749. White MK, Khalili K, Interaction of retinoblastoma protein family members with large T-antigen of primate polyomaviruses. Oncogene 25:38(5286-93)2006 Aug 28

16741955. Claudio PP, Cui J, Ghafouri M, Mariano C, White MK, Safak M, Sheffield JB, Giordano A, Khalili K, Amini S, Sawaya BE, Cdk9 phosphorylates p53 on serine 392 independently of CKII. J Cell Physiol 208:3(602-12)2006 Sep

16741925. Darbinian N, White MK, Khalili K, Regulation of the Pur-alpha promoter by E2F-1. J Cell Biochem 99:4(1052-63)2006 Nov 1

16725168. White MK, Gorrill TS, Khalili K, Reciprocal transactivation between HIV-1 and other human viruses. Virology 352:1(1-13)2006 Aug 15

16690919. Gorrill T, Feliciano M, Mukerjee R, Sawaya BE, Khalili K, White MK, Activation of early gene transcription in polyomavirus BK by human immunodeficiency virus type 1 Tat. J Gen Virol 87:Pt 6(1557-66)2006 Jun

16629416. Khalili K, White MK, Human demyelinating disease and the polyomavirus JCV. Mult Scler 12:2(133-42)2006 Apr

16626043. Khalili K, Gordon J, White MK, The polyomavirus, JCV and its involvement in human disease. Adv Exp Med Biol 577:(274-87)2006

16619477. Enam S, Gan DD, White MK, Del Valle L, Khalili K, Regulation of human neurotropic JCV in colon cancer cells. Anticancer Res 26:2A(833-41)2006 Mar-Apr

16557392. Piña-Oviedo S, De León-Bojorge B, Cuesta-Mejías T, White MK, Ortiz-Hidalgo C, Khalili K, Del Valle L, Glioblastoma multiforme with small cell neuronal-like component: association with human neurotropic JC virus. Acta Neuropathol 111:4(388-96)2006 Apr

16497349. Akan I, Sariyer IK, Biffi R, Palermo V, Woolridge S, White MK, Amini S, Khalili K, Safak M, Human polyomavirus JCV late leader peptide region contains important regulatory elements. Virology 349:1(66-78)2006 May 25

16219459. White MK, Khalili K, Expression of JC virus regulatory proteins in human cancer: potential mechanisms for tumourigenesis. Eur J Cancer 41:16(2537-48)2005 Nov

16135803. Amini S, Mameli G, Del Valle L, Skowronska A, Reiss K, Gelman BB, White MK, Khalili K, Sawaya BE, p73 Interacts with human immunodeficiency virus type 1 Tat in astrocytic cells and prevents its acetylation on lysine 28. Mol Cell Biol 25:18(8126-38)2005 Sep

15982744. White MK, Gordon J, Reiss K, Del Valle L, Croul S, Giordano A, Darbinyan A, Khalili K, Human polyomaviruses and brain tumors. Brain Res Brain Res Rev 50:1(69-85)2005 Dec 1

15630684. Del Valle L, White MK, Enam S, Piña Oviedo S, Bromer MQ, Thomas RM, Parkman HP, Khalili K, Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma. Cancer 103:3(516-27)2005 Feb 1

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