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Journal of Virology, September 2007, p. 9653-9664, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00568-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Enhanced Phosphorylation of Transcription Factor Sp1 in Response to Herpes Simplex Virus Type 1 Infection Is Dependent on the Ataxia Telangiectasia-Mutated Protein{triangledown}

Satoko Iwahori,1 Noriko Shirata,1 Yasushi Kawaguchi,2 Sandra K. Weller,3 Yoshitaka Sato,1 Ayumi Kudoh,1 Sanae Nakayama,1 Hiroki Isomura,1 and Tatsuya Tsurumi1*

Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan,1 Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan,2 Department of Molecular, Microbial and Structural Biology MC3205, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 060303

Received 19 March 2007/ Accepted 26 June 2007

The ataxia telangiectasia-mutated (ATM) protein, a member of the related phosphatidylinositol 3-like kinase family encoded by a gene responsible for the human genetic disorder ataxia telangiectasia, regulates cellular responses to DNA damage and viral infection. It has been previously reported that herpes simplex virus type 1 (HSV-1) infection induces activation of protein kinase activity of ATM and hyperphosphorylation of transcription factor, Sp1. We show that ATM is intimately involved in Sp1 hyperphosphorylation during HSV-1 infection rather than individual HSV-1-encoded protein kinases. In ATM-deficient cells or cells silenced for ATM expression by short hairpin RNA targeting, hyperphosphorylation of Sp1 was prevented even as HSV-1 infection progressed. Mutational analysis of putative ATM phosphorylation sites on Sp1 and immunoblot analysis with phosphopeptide-specific Sp1 antibodies clarified that at least Ser-56 and Ser-101 residues on Sp1 became phosphorylated upon HSV-1 infection. Serine-to-alanine mutations at both sites on Sp1 considerably abolished hyperphosphorylation of Sp1 upon infection. Although ATM phosphorylated Ser-101 but not Ser-56 on Sp1 in vitro, phosphorylation of Sp1 at both sites was not detected at all upon infection in ATM-deficient cells, suggesting that cellular kinase(s) activated by ATM could be involved in phosphorylation at Ser-56. Upon viral infection, Sp1-dependent transcription in ATM expression-silenced cells was almost the same as that in ATM-intact cells, suggesting that ATM-dependent phosphorylation of Sp1 might hardly affect its transcriptional activity during the HSV-1 infection. ATM-dependent Sp1 phosphorylation appears to be a global response to various DNA damage stress including viral DNA replication.

* Corresponding author. Mailing address: Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Phone and fax: 81-52-764-2979. E-mail: ttsurumi{at}aichi-cc.jp

{triangledown} Published ahead of print on 3 July 2007.

Journal of Virology, September 2007, p. 9653-9664, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00568-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sampath, P., DeLuca, N. A. (2008). Binding of ICP4, TATA-Binding Protein, and RNA Polymerase II to Herpes Simplex Virus Type 1 Immediate-Early, Early, and Late Promoters in Virus-Infected Cells. J. Virol. 82: 2339-2349 [Abstract] [Full Text]  
  • Olofsson, B. A., Kelly, C. M., Kim, J., Hornsby, S. M., Azizkhan-Clifford, J. (2007). Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase. Mol Cancer Res 5: 1319-1330 [Abstract] [Full Text]  


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