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Journal of Virology, May 2008, p. 4862-4873, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.01202-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Casein Kinase II Motif-Dependent Phosphorylation of Human Papillomavirus E7 Protein Promotes p130 Degradation and S-Phase Induction in Differentiated Human Keratinocytes{triangledown}

Nicholas J. Genovese,{dagger} N. Sanjib Banerjee,{dagger} Thomas R. Broker, and Louise T. Chow*

University of Alabama at Birmingham, Biochemistry and Molecular Genetics, 1918 University Boulevard, McCallum Building 510, Birmingham, Alabama 35294-0005

Received 1 June 2007/ Accepted 27 February 2008

The E7 proteins of human papillomaviruses (HPVs) promote S-phase reentry in differentiated keratinocytes of the squamous epithelia to support viral DNA amplification. In this study, we showed that nuclear p130 was present in the differentiated strata of several native squamous epithelia susceptible to HPV infection. In contrast, p130 was below the level of detection in HPV-infected patient specimens. In submerged and organotypic cultures of primary human keratinocytes, the E7 proteins of the high-risk mucosotrophic HPV-18, the benign cutaneous HPV-1, and, to a lesser extent, the low-risk mucosotropic HPV-11 destabilized p130. This E7 activity depends on an intact pocket protein binding domain and a casein kinase II (CKII) phosphorylation motif. Coimmunoprecipitation experiments showed that both E7 domains were important for binding to p130 in extracts of organotypic cultures. Metabolic labeling in vivo demonstrated that E7 proteins were indeed phosphorylated in a CKII motif-dependent manner. Moreover, the efficiencies of the E7 proteins of various HPV types or mutations to induce S-phase reentry in spinous cells correlated with their relative abilities to bind and to destabilize p130. Collectively, these data support the notion that p130 controls the homeostasis of the differentiated keratinocytes and is therefore targeted by E7 for degradation to establish conditions permissive for viral DNA amplification.

* Corresponding author. Mailing address: University of Alabama at Birmingham, Biochemistry and Molecular Genetics, 1918 University Boulevard, McCallum Building 510, Birmingham, AL 35294-0005. Phone: (205) 975-8300. Fax: (205) 975-6075. E-mail: LTChow{at}uab.edu

{triangledown} Published ahead of print on 5 March 2008.

{dagger} N.J.G. and N.S.B. contributed equally to this study.

Journal of Virology, May 2008, p. 4862-4873, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.01202-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, X., Wang, H.-K., McCoy, J. P., Banerjee, N. S., Rader, J. S., Broker, T. R., Meyers, C., Chow, L. T., Zheng, Z.-M. (2009). Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA 15: 637-647 [Abstract] [Full Text]  
  • Wang, H.-K., Duffy, A. A., Broker, T. R., Chow, L. T. (2009). Robust production and passaging of infectious HPV in squamous epithelium of primary human keratinocytes. Genes Dev. 23: 181-194 [Abstract] [Full Text]  


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