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Activation of the JC Virus Tat- Response Transcriptional Control

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Activation of the JC Virus Tat- Response Transcriptional Control Corrections Proc. Natl. Acad. Sci. USA 94 (1997) 9511 Microbiology. In the article “Activation of the JC virus Tat- Physiology. In the article “Activation of heteromeric G pro- response transcriptional control element by association of the tein-gated inward rectifier K1 channels overexpressed by Tat protein of human immunodeficiency virus 1 with cellular adenovirus gene transfer inhibits the excitability of hippocam- protein Pura” by Chavdar P. Krachmarov, Lara G. Chepenik, pal neurons” by Markus U. Ehrengruber, Craig A. Doupnik, Sharon Barr-Vagell, Kamel Khalili, and Edward M. Johnson, Youfeng Xu, Justine Garvey, Mark C. Jasek, Henry A. Lester, which appeared in number 24, November 26, 1996, of Proc. and Norman Davidson, which appeared in number 13, June 24, Natl. Acad. Sci. USA (93, 14112–14117), the authors wish to 1997, of Proc. Natl. Acad. Sci. USA (94, 7070–7075), the note that the sequences of two deletion mutants were incor- authors wish to correct the institutional affiliation of Dr. D. E. rectly described. In the left column on page 14116, lines 13–16 Clapham, which was printed incorrectly on page 7070 as should read: “We have tested the effect of two additional Pura McMaster University. Dr. Clapham’s correct affiliation is mutants on transactivation of the JVC late promoter in vivo. Harvard University Medical School. One mutant, Pura 1-215, is illustrated in Fig. 3. The other mutant was PuraD72-216.” The last three sentences of this paragraph should be deleted. Please note that the experiments mentioned in this correction were not included in any of the figures or tables and were not mentioned elsewhere in the text. The essential results and conclusions as stated in the Abstract are unchanged. Downloaded by guest on September 29, 2021 Proc. Natl. Acad. Sci. USA Vol. 93, pp. 14112–14117, November 1996 Microbiology Activation of the JC virus Tat-responsive transcriptional control element by association of the Tat protein of human immunodeficiency virus 1 with cellular protein Pura (AIDSyprogressive multifocal leukoencephalopathyyglial cellsypapovavirusPurA) CHAVDAR P. KRACHMAROV*, LARA G. CHEPENIK†,SHARON BARR–VAGELL*, KAMEL KHALILI†, AND EDWARD M. JOHNSON*‡ *Department of Pathology and Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, Box 1194, New York, NY 10029; and †Molecular Neurovirology Section, Jefferson Institute of Molecular Medicine, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South Tenth Street, Philadelphia, PA 19107 Communicated by Thomas Shenk, Princeton University, Princeton, NJ, September 5, 1996 (received for review May 28, 1996) ABSTRACT JC virus is activated to replicate in glial cells scriptional activation by Tat requires interaction with a cellular of many AIDS patients with neurological disorders. In human protein and the Tat-responsive upTAR element located in the glial cells, the human immunodeficiency virus 1 (HIV-1) Tat JCV late region promoter upstream of the transcriptional start protein activates the major late promoter of JC virus through sites. Tat itself does not bind this element (23). Since the a Tat-responsive DNA element, termed upTAR, which is a upTAR element contains consensus binding sites for Pura,an recognition site for cellular Pura, a sequence-specific single- evolutionarily conserved nuclear protein (24–26), we sought to stranded DNA binding protein implicated in cell cycle control determine whether this protein would interact with both Tat of DNA replication and transcription. Tat interacts with two and upTAR. leucine-rich repeats in Pura to form a complex that can be Pura is a nuclear protein of 322 aa (25, 26) that has been immunoprecipitated from cell extracts. Tat enhances the implicated in control of both gene transcription (27–29) and ability of purified glutathione S-transferase–Pura (GST– DNA replication (24, 26, 30). In avian cells, Pura mediates Pura) to bind the upTAR element. Tat acts synergistically with effects of Rous sarcoma virus on cellular gene transcription Pura, in a cell-cycle-dependent manner, to activate transcrip- (28). Pura contains a region with limited homology to the tion at an upTAR element placed upstream of a heterologous simian virus 40 large tumor antigen (26), and this region is promoter. Since Pura is ubiquitously expressed in human implicated in the binding of each of these proteins to Rb, the cells and since PUR elements are located near many promoters retinoblastoma tumor suppressor gene product (31). Pura is a and origins of replication, the Tat–Pura interaction may be single-stranded DNA binding protein with specific affinity for implicated in effects of HIV-1 throughout the full range of repeats of the sequence GGN (25). The JCV upTAR element, HIV-1-infected cells. located just distal to the viral origin of DNA replication relative to the late mRNA start sites, contains the sequence JC virus (JCV) is the etiologic agent of progressive multifocal GGAGGCGGAGGC, which is essential for Tat responsive- leukoencephalopathy, a demyelinating neurodegenerative dis- ness (23). Herein we show that human Pura has a specific ease. While JCV is normally latent in humans, it is activated in affinity for the Tat protein in glial cells and that Tat and Pura the central nervous systems of certain immunocompromised act synergistically in vivo to enhance transcription at the JCV individuals. A high preponderance of JCV infection in brains Tat-responsive upTAR element. of AIDS patients has suggested that the human immunodefi- ciency virus 1 (HIV-1) itself, independently of its effects on the MATERIALS AND METHODS immune system, may play a role in activation (1, 2). JCV has a highly specific tropism for glial cells. HIV-1 also infects glial Plasmids and Vectors. Plasmids used for transfection were cells in the brain, and aside from the as yet undemonstrated constructed as follows. Plasmid UP-2 is vector pBLCat-2, possibility of coinfection, JCV-infected cells would be acces- containing the Escherichia coli chloramphenicol acetyltrans- sible to the HIV-1 Tat protein (3–5). ferase (CAT) gene linked to the herpes simplex virus thymi- The Tat protein encoded by HIV-1 is an RNA-binding dine kinase (TK) gene promoter and, upstream of the pro- protein that stimulates transcription at the viral long terminal moter, the upTAR element, synthesized as follows with 4-bp repeat promoter through specific interaction with an element restriction site ends: 59-AGCTTGGAGGCGGAGGCG-39 (transactivation region, or TAR) present within the 59 un- and 39-ACCTCCGCCTCCGCAGCT-59. Plasmid UP-3 is translated leader of HIV-1 transcripts (6–12). While the pBLCat-2 containing the upTAR element mutated as follows: precise mechanism of Tat activation is unknown, evidence 59-AGCTTGGAAAGTTAGGCG-39 and 39-ACCTT- suggests that the protein acts on transcription by introducing TCAATCCGCAGCT-59. Plasmid pActin-Tat has been de- associated cellular factors for either initiation, elongation or scribed (22). Plasmid pEBV-Pur contains the 1.1-kb Pura antitermination into the vicinity of the transcriptional appa- cDNA of pPUR6 (25) under control of the Epstein–Barr virus ratus (8, 13–15). While cellular proteins have been identified promoter. that bind to Tat (16–20), the mechanism by which these might Immunoprecipitation. Glioblastoma cell line 5–10, consti- activate transcription of any given gene is not known. The 59 tutively synthesizing Tat expressed under control of the simian leaders of certain of the late JCV transcripts contain elements virus 40 late promoter, was cultured in Dulbecco’s modified homologous to TAR (21), and transcription of these mRNAs is strongly stimulated by Tat (22). Furthermore, JCV tran- Abbreviations: JCV, polyoma virus JC; GST, glutathione S- transferase; HIV-1, human immunodeficiency virus 1; CAT, chlor- amphenicol acetyltransferase; LRR, leucine-rich repeat; TK, thymi- The publication costs of this article were defrayed in part by page charge dine kinase. payment. This article must therefore be hereby marked ‘‘advertisement’’ in ‡To whom reprint requests should be addressed. e-mail: johnson@ accordance with 18 U.S.C. §1734 solely to indicate this fact. msvax.mssm.edu. 14112 Microbiology: Krachmarov et al. Proc. Natl. Acad. Sci. USA 93 (1996) 14113 Eagle’s medium (DMEM) containing 10% fetal bovine serum of Tat and Pura to form a complex in cells where both proteins in 75-cm2 plates to 5 3 105 cells per plate. Extracts of 107 cells are present. The human glioblastoma cell line 5–10 has been were prepared by lysis at 08C in 4.5 ml of Lysis 150 buffer (31) derived from line U-87MG transfected with a vector for supplemented to 250 mM NaCl. After 2 min in lysis buffer, expression of the tat gene linked to a simian virus 40 promoter extracts were clarified by centrifugation at 14,000 3 g for 4 min and synthesizes Tat constitutively (33). These cells also contain in an Eppendorf centrifuge. After addition of 1.5 ml of Lysis Pura, as does every mammalian tissue thus far tested. Fig. 1A, 150 buffer with no NaCl, monoclonal antibody 9C12 (2.0 mg) a Western blot with anti-Tat antibody, shows that Tat and Pura was added to 1.0-ml aliquots of extract. After incubation at 08C can be immunoextracted as a complex from lysates of 5–10 cells for 30 min, magnetic beads coupled to sheep anti-mouse using a monoclonal antibody to Pura. Lysates of 5–10 cells antibody (Dynal, Great Neck, NY; 500 mg of beads coupled to possess a protein migrating at approximately 16 kDa that approximately 5 mg of antibody) were added to each 1-ml reacts with the anti-Tat antibody, as well as a larger aggregated aliquot. After 2 hr at 48C with gentle shaking, beads were Tat form (left lane). The 5–10 cells possess a large amount of collected by magnetism and washed five times with 1 ml of 0.15 this aggregated Tat form, which may be an artifact of overex- M NaCly0.015 M sodium citrate (pH 7.0) containing 1 mM pression.
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