E7 Abolishes Raf-Induced Arrest via Mislocalization of p21Cip1

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American Society for Microbiology

RESUMO

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.

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