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Mahmut Safak, PhDMahmut Safak, PhD

 

Associate Professor, Neuroscience

Associate Professor, Neurovirology

Location: Room 757 MERB

Telephone:  215-707-6338

Fax:  215-707-4888

Email: msafak@temple.edu

 

Department of Neuroscience

Center for Neurovirology

 

Educational Background:

 

PhD, Biochemistry and Molecular Pharmacology - 1998

Thomas Jefferson University

Philadelphia, PA

 

Postdoctoral Fellowship - 2000

Drexel (MCP Hahnemann) University School of Medicine

Philadelphia, PA

 

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Research Interests:

 

To understand the molecular mechanisms involved in JC virus (JCV) gene transcription and replication at the molecular level in order to develop molecular therapeutics that effectively inhibit viral replication in the central nervous system and thereby JCV-caused disease, progressive multifocal encephalopathy (PML).

 

Research Summary
Our laboratory’s research interest revolves around understanding transcriptional and replicational regulation of JC virus (JCV) by viral and cellular factors. JCV, a human polyomavirus, asymptomatically infects most individuals early in life and persists in the body. In immunocompromised individuals, however, JCV may lytically infect oligodentrocytes in the central nervous system and cause a white matter disease known as progressive multifocal leukoencephalopathy. Approximately 5-8% of AIDS patients now succumb to this disease. Numereous studies have shown that JCV is an oncogenic agent and has the ability to induce a wide variety of tumors in rodents and in non-human primates. Recent reports indicate the possible association of JCV with certain human tumors. Our group particularly interested in functional analysis of two JCV regulatory proteins, agnoprotein and small t antigen (t-Ag) in JCV biology.


Agnoprotein is a small regulatory protein encoded by the leader sequences of the JCV late genome. Recent investigation of its function through mutational analysis showed that not only agnoprotein itself but its coding sequences plays critical roles in JCV regulation. In particular, deletion analysis of the agno gene resulted in complete abrogation of the JCV activity suggesting that its coding region may contain some regulatory cis-acting DNA elements to which unknown nuclear protein complexes bind and regulate the JCV life cycle. In fact, nuclease protection analysis of the entire coding region of this protein revealed three protected regions and further analysis of the protein complexes that interact with one of the protected regions by Mass Spectroscopy identified several cellular factors, some of which were shown to be involved in DNA helicase, replication, repair and gene regulation. Thus, we are interested in further analysis of the agnoprotein, its coding region and the factors that interact with this region.


Small t-Ag is produced due to alternative splicing of JCV early transcripts. We are also interested in functional analysis of this protein in JCV regulation and cell transformation using different experimental model systems. The functional activity of this protein in both areas is completely unknown. However, our recent findings indicate that small t-Ag has the ability to promote cell cycle progression perhaps through the activation of cell growth and proliferation pathways. Our goal is then to investigate the role of this protein in JCV regulation as well as to delineate the molecular pathways involved in small t-Ag-induced cell proliferation.

 

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PUBMED PUBLICATIONS :


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

25139865. Coric P, Saribas AS, Abou-Gharbia M, Childers W, White MK, Bouaziz S, Safak M, Correction for Coric et al., Nuclear Magnetic Resonance Structure Revealed that the Human Polyomavirus JC Virus Agnoprotein Contains an a-Helix Encompassing the Leu/Ile/Phe-Rich Domain. J Virol 88:18(11000)2014 Sep 15

24672035. Coric P, Saribas AS, Abou-Gharbia M, Childers W, White MK, Bouaziz S, Safak M, Nuclear Magnetic Resonance Structure Revealed that the Human Polyomavirus JC Virus Agnoprotein Contains an a-Helix Encompassing the Leu/Ile/Phe-Rich Domain. J Virol 88:12(6556-75)2014 Jun 15

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

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

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

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

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

21731577. Saribas AS, Ozdemir A, Lam C, Safak M, JC virus-induced Progressive Multifocal Leukoencephalopathy. Future Virol 5:3(313-323)2010 May

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

19442856. Sariyer IK, Safak M, Gordon J, Khalili K, Generation and characterization of JCV permissive hybrid cell lines. J Virol Methods 159:1(122-6)2009 Jul

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

18353419. Sariyer IK, Khalili K, Safak M, Dephosphorylation of JC virus agnoprotein by protein phosphatase 2A: inhibition by small t antigen. Virology 375:2(464-79)2008 Jun 5

18230652. Staniszewska I, Sariyer IK, Lecht S, Brown MC, Walsh EM, Tuszynski GP, Safak M, Lazarovici P, Marcinkiewicz C, Integrin alpha9 beta1 is a receptor for nerve growth factor and other neurotrophins. J Cell Sci 121:Pt 4(504-13)2008 Feb 15

18022798. Khalili K, Sariyer IK, Safak M, Small tumor antigen of polyomaviruses: role in viral life cycle and cell transformation. J Cell Physiol 215:2(309-19)2008 May

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

16571806. Sariyer IK, Akan I, Palermo V, Gordon J, Khalili K, Safak M, Phosphorylation mutants of JC virus agnoprotein are unable to sustain the viral infection cycle. J Virol 80:8(3893-903)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

15573377. Khalili K, White MK, Sawa H, Nagashima K, Safak M, The agnoprotein of polyomaviruses: a multifunctional auxiliary protein. J Cell Physiol 204:1(1-7)2005 Jul

12894576. Khalili K, Del Valle L, Wang JY, Darbinian N, Lassak A, Safak M, Reiss K, T-antigen of human polyomavirus JC cooperates withIGF-IR signaling system in cerebellar tumors of the childhood-medulloblastomas. Anticancer Res 23:3A(2035-41)2003 May-Jun

12758167. Abraham S, Sawaya BE, Safak M, Batuman O, Khalili K, Amini S, Regulation of MCP-1 gene transcription by Smads and HIV-1 Tat in human glial cells. Virology 309:2(196-202)2003 May 10

12709864. Safak M, Khalili K, An overview: Human polyomavirus JC virus and its associated disorders. J Neurovirol 9 Suppl 1:(3-9)2003

12692226. Kim J, Woolridge S, Biffi R, Borghi E, Lassak A, Ferrante P, Amini S, Khalili K, Safak M, Members of the AP-1 family, c-Jun and c-Fos, functionally interact with JC virus early regulatory protein large T antigen. J Virol 77:9(5241-52)2003 May

12477869. Sadowska B, Barrucco R, Khalili K, Safak M, Regulation of human polyomavirus JC virus gene transcription by AP-1 in glial cells. J Virol 77:1(665-72)2003 Jan

12165856. Darbinyan A, Darbinian N, Safak M, Radhakrishnan S, Giordano A, Khalili K, Evidence for dysregulation of cell cycle by human polyomavirus, JCV, late auxiliary protein. Oncogene 21:36(5574-81)2002 Aug 15

11907223. Safak M, Sadowska B, Barrucco R, Khalili K, Functional interaction between JC virus late regulatory agnoprotein and cellular Y-box binding transcription factor, YB-1. J Virol 76:8(3828-38)2002 Apr

11517404. Safak M, Khalili K, Physical and functional interaction between viral and cellular proteins modulate JCV gene transcription. J Neurovirol 7:4(288-92)2001 Aug

11302687. Ansari SA, Safak M, Del Valle L, Enam S, Amini S, Khalili K, Cell cycle regulation of NF-kappa b-binding activity in cells from human glioblastomas. Exp Cell Res 265:2(221-33)2001 May 1

11152520. Safak M, Barrucco R, Darbinyan A, Okada Y, Nagashima K, Khalili K, Interaction of JC virus agno protein with T antigen modulates transcription and replication of the viral genome in glial cells. J Virol 75:3(1476-86)2001 Feb

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