The Adenovirus E4-6/7 Protein Directs Nuclear Localization of E2F-4 Via an Arginine-rich Motif

E2F transcription factors are key participants in the regulation of proliferation, apoptosis, and differentiation in mammalian cells. E2Fs are negatively regulated by members of the retinoblastoma protein (pRb) family. During adenovirus (Ad) infection, viral proteins that displace pRb family members from E2Fs and recruit E2F complexes to viral and cellular promoter regions are expressed. This recruitment of E2F involves the induction of stable E2F binding to inverted E2F binding sites in the Ad E2a and cellular E2F-1 promoters and induces both viral and cellular gene expression. E2F-4 has abundant E2F activity within cells, and the majority of E2F-4 in asynchronous cells is found in the cytoplasm. Upon expression of the adenovirus E4-6/7 protein, a significant portion of E2F-4 is translocated to the nucleus, and its activity constitutes the majority of Ad-induced nuclear E2F DNA binding activity. This redirection of E2F-4 from cytoplasm to the nucleus requires an N-terminal arginine-rich nuclear localization sequence within E4-6/7. The directed targeting of E4-6/7 to the nucleus is important for the function of this protein in the context of viral infection. This function of E4-6/7 has a redundant component as well as nonredundant components in cooperation with the adenovirus E1A oncoproteins to deregulate and usurp host cell E2F function.