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Molecular and Cellular Biology, October 2002, p. 7041-7052, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7041-7052.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

E7 Abolishes Raf-Induced Arrest via Mislocalization of p21Cip1

Thomas F. Westbrook,1 Don X. Nguyen,1 Barry R. Thrash,2 and Dennis J. McCance1,3*

Department of Microbiology and Immunology,1 Department of Biochemistry and Biophysics,2 The Cancer Center, University of Rochester, Rochester, New York 146423

Received 19 March 2002/ Returned for modification 18 June 2002/ Accepted 11 July 2002

The cellular response to oncogenic Ras depends upon the presence or absence of cooperating mutations. In the absence of immortalizing oncogenes or genetic lesions, activation of the Ras/Raf pathway results in a p21Cip1-dependent cellular arrest. The human papillomavirus oncoprotein E7 transforms primary cells in cooperation with Ras and abolishes p21Cip1-mediated growth arrest in the presence of various antimitogenic signals. Here we have utilized a conditional Raf molecule to investigate the effects of E7 on p21Cip1 function in the context of Raf-induced cellular arrest. E7 bypassed Raf-induced arrest and alleviated inhibition of cyclin E-CDK2 without suppressing Raf-specific synthesis of p21Cip1 or derepressing p21Cip1-associated CDK2 complexes. Activation of Raf led to nuclear accumulation of p21Cip1, and we provide evidence that this effect is mediated by inhibition of Akt, a regulator of p21Cip1 localization. Loss of Akt activity appears to be an important event in the cellular arrest associated with Raf-induction, since maintenance of Akt activity was necessary and sufficient to bypass Raf-induced arrest. In agreement, expression of E7 sustained Akt activity and reduced nuclear accumulation of p21Cip1, resulting in decreased association between p21Cip1 and cyclin E-CDK2. Taken together, these data suggest that E7 inhibits p21Cip1 function in the context of Raf signaling by altering Raf-Akt antagonism and preventing the proper subcellular localization of p21Cip1. We propose that E7 elicits a proliferative response to Raf signaling by targeting p21Cip1 function via a novel mechanism.

* Corresponding author. Mailing address: University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 672, Rochester, NY 14642. Phone: (585) 275-0101. Fax: (585) 473-9573. E-mail: dennis_mccance{at}urmc.rochester.edu.

Molecular and Cellular Biology, October 2002, p. 7041-7052, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7041-7052.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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