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 publications, contact information
Photo: Research Interests The current focus of my laboratory is on Gene Expression, Genomics, and Proteomics of HIV-1 and HTLV-1 infected cells. HIV-1 is the etiological agent of AIDS and HTLV-1 is associated with adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HIV-1 infected cells are associated with apoptosis and cell death, whereas HTLV-1 infection is associated with anti-apoptosis or malignancy. Activated HIV-1 and HTLV-1 transcription requires the viral transactivators Tat and Tax, respectively. In addition, the chromatin environment greatly regulates transcription, through allowing access to the viral promoter as well serving as a platform to assemble large protein transcriptional complexes. My lab is investigating the intricate details of viral transcription regulation, focusing heavily on the components of the protein transcriptional complexes, post-translational modifications of transcription factors, and the role of chromatin remodeling complexes (BRG1) on viral transcription. Most viral therapeutics target the virus itself, providing very specific effects and limiting side-effects on uninfected cells. However, this strategy of drug design often results in resistant viruses, especially among RNA viruses. Therefore, the focus of my lab has turned to drugs that target cellular proteins that are essential for viral replication, but not for cellular viability. Cyclin dependent kinases (CDKs), especially CDK2 and CDK9, are excellent cellular targets, which have proven to be critical for viral transcription, but not for cell survival. Therefore, my lab is identifying novel next generation CDK inhibitors that are potent HIV-1 and HTLV-1 therapeutics. My lab has recently developed a novel HIV-1 humanized mouse model. T his new mouse model utilizes Rag2 −/−γc −/− mice that are sub-lethally irradiated to kill the mouse immune system. Mice are then implanted with h uman cord blood stem cells, which are allowed to reconstitute a human immune system in vivo followed by infection with HIV-1. This mouse model is essential for our therapeutic studies, as it allows the testing of promising viral inhibitors in a non-primate model of HIV disease. The Proteomic approach allows a more global analysis of proteins that are altered after infection with HIV-1 or HTLV-1. We are especially interested in understanding the changes induced in the cellular membrane proteome of cells chronically infected with HIV-1 and to determine how such changes are relevant to the latency phenomenon. Through a membrane proteomic study, we have recently demonstrated that the anti-apoptotic proteins Bruton’s tyrosine kinase (BTK) and the X-linked inhibitor of apoptosis (XIAP) are up-regulated in the membrane proteome of chronically infected T cell lines compared to their parental cell lines. We are examining the functional significance of this over expression and the therapeutic effects of inhibiting these proteins. Recently, a third member of the HTLV group was discovered, HTLV-3 . This virus is present at least in Central Africa, but its prevalence worldwide is currently unknown. Our lab was the first to work with the discoverers of this virus to develop the role of the potentially transforming protein Tax3.The viral transactivator Tax protein has been demonstrated to have a central role in the immortalization and transformation of HTLV-1 infected cells. We are investigating whether HTLV-3 is, as HTLV-1, an oncogenic virus and whether the Tax3 is a transforming protein. Selected Publications ( From total of 103-last 3 years listed ) Top Zhou M, Haung K, Jung KJ, Cho WK, Klase Z, Kashanchi F, Pise-Masion CA, Brady JN. Bromodomain protein Brd4 regulates HIV transcription through phosphorylation of CDK9 at threonine 29. J. Virol. 2008 Oct 29. Van Duyne R, Kehn-Hall K, Klase Z, Easley R, Heydarian M, Saifuddin M, Wu W, Kashanchi F. Retroviral proteomics and interactomes: intricate balances of cell survival and viral replication. Expert Rev Proteomics 2008 Jun;5(3):507-28. Van Duyne R, Easley R, Wu W, Berro R, Pedanti C, Klase Z, Kehn-Hall K, Flynn SK, Symer DE, Kashanchi F. Lysine methylation of HIV-1 Tat regulates transcriptional activity of the viral LTR. Retrovirology 2008 May 22;5:40. Berro R, Pedati C, Kehn-Hall K, Wu W, Klase Z, Even Y, Geneviere AM, Ammosova T, Nekhai S, Kashanchi F. CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing. J. Virol 2008 Jul;82(14):7155-66. Van Duyne R, Cardenas J, Easley R, Wu W, Kehn-Hall K, Klase Z, Mendez S, Zeng C, Chen H, Saifuddin M, Kashanchi F. Effect of transcription peptide inhibitors on HIV-1 replication. Virology. 2008 Jul 5; 376(2):308-22. Chevalier SA, Ko NL, Calattini S, Mallet A, Prevost MC, Kehn K, Brady JN, Kashanchi F, Gessain A, Mahieux R. Construction and characterization of a human T-cell lymphotropic virus type 3 infectious molecular clone. J. Virol. 2008 Jul;82(13):6747-52. Wu W, Kehn-Hall K, Pedati C, Zweier L, Castro I, Klase Z, Dowd CS, Dubrovsky L, Bukrinsky M, Kashanchi F. Drug 9AA reactivates p21/Waf1 and Inhibits HIV-1 progeny formation. Virol J. 2008 Mar 18;5:41. Ku SC, Lee J, Lau J, Gurumurthy M, Ng R, Lwa SH, Lee J, Klase Z, Kashanchi F, Chao SH. XBP-1, a novel human T-lymphotropic virus type 1 (HTLV-1) tax binding protein, activates HTLV-1 basal and tax-activated transcription. J Virol. 2008 May; 82(9):4343-53. Klase ZA, Van Duyne R, Kashanchi F. Identification of potential drug targets using genomics and proteomics: a systems approach. Adv Pharmacol. 2008;56:327-68. Klase Z, Kale P, Winograd R, Gupta MV, Heydarian M, Berro R, McCaffrey T, KashanchiF. HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol Biol. 2007 Jul 30;8:63. Kehn K, Berro R, Alhaj A, Bottazzi ME, Yeh WI, Klase Z, Van Duyne R, Fu S, Kashanchi F. Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells. Oncogene. 2007 Aug 2;26(35):5060-9. Berro R, de la Fuente C, Klase Z, Kehn K, Parvin L, Pumfery A, Agbottah E, Vertes A, Nekhai S, Kashanchi F. Identifying the membrane proteome of HIV-1 latently infected cells. J Biol Chem. 2007 Mar 16;282(11):8207-18. Ammosova T, Berro R, Jerebtsova M, Jackson A, Charles S, Klase Z, Southerland W, Gordeuk VR, Kashanchi F, Nekhai S. Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription. Retrovirology. 2006 Nov 3;3:78. Pumfery A, de la Fuente C, Kashanchi F. HTLV-1 Tax: centrosome amplification and cancer. Retrovirology. 2006 Aug 9;3:50. Agbottah E, Deng L, Dannenberg LO, Pumfery A, Kashanchi F. Effect of SWI/SNF chromatin remodeling complex on HIV-1 Tat activated transcription. Retrovirology. 2006 Aug 7;3(1):48 de la Fuente C, Gupta MV, Klase Z, Strouss K, Cahan P, McCaffery T, Galante A, Soteropoulos P, Pumfery A, Fujii M, Kashanchi F. Involvement of HTLV-I Tax and CREB in aneuploidy: A bioinformatics approach. Retrovirology. 2006 Jul 5;3(1):43 Berro R, Kehn K, de la Fuente C, Pumfery A, Adair R, Wade J, Colberg-Poley AM, Hiscott J, Kashanchi F. Acetylated Tat regulates human immunodeficiency virus type 1 splicing through its interaction with the splicing regulator p32. J Virol. 2006 Apr;80(7): 3189-204. Agbottah E, Zhang N, Dadgar S, Pumfery A, Wade JD, Zeng C, Kashanchi F. Inhibition of HIV-1 virus replication using small soluble Tat peptides. Virology. 2006 Feb 20;345(2): 373-89. Contact Information Top Fatah Kashanchi, Ph.D.
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