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Journal of Virology, October 2004, p. 10410-10419, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10410-10419.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Murine Coronavirus Nonstructural Protein p28 Arrests Cell Cycle in G0/G1 Phase

Chun-Jen Chen,{dagger} Kazuo Sugiyama, Hideyuki Kubo, Cheng Huang, and Shinji Makino*

Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, Texas

Received 4 March 2004/ Accepted 11 May 2004

Murine coronavirus mouse hepatitis virus (MHV) gene 1 encodes several nonstructural proteins. The functions are unknown for most of these nonstructural proteins, including p28, which is encoded at the 5' end of the MHV genome. Transient expression of cloned p28 in several different cultured cells inhibited cell growth, indicating that p28 expression suppressed cell proliferation. Expressed p28 was exclusively localized in the cytoplasm. Cell cycle analysis by flow cytometry demonstrated that p28 expression induced G0/G1 cell cycle arrest. Characterization of various cellular proteins that are involved in regulating cell cycle progression demonstrated that p28 expression resulted in an accumulation of hypophosphorylated retinoblastoma protein (pRb), tumor suppressor p53, and cyclin-dependent kinase (Cdk) inhibitor p21Cip1. Expression of p28 did not alter the amount of p53 transcripts yet increased the amount of p21Cip1 transcripts, suggesting that p28 expression increased p53 stability and that p21Cip1 was transcriptionally activated in a p53-dependent manner. Our present data suggest the following model of p28-induced G0/G1 cell cycle arrest. Expressed cytoplasmic p28 induces the stabilization of p53, and accumulated p53 causes transcriptional upregulation of p21Cip1. The increased amount of p21Cip1 suppresses cyclin E/Cdk2 activity, resulting in the inhibition of pRb hyperphosphorylation. Accumulation of hypophosphorylated pRb thus prevents cell cycle progression from G0/G1 to S phase.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555-1019. Phone: (409) 772-2323. Fax: (409) 772-5065. E-mail: shmakino{at}utmb.edu.

{dagger} Present address: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655.

Journal of Virology, October 2004, p. 10410-10419, Vol. 78, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.19.10410-10419.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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