POSTTRANSCRIPTIONAL INDUCTION OF P21CIP1 PROTEIN BY HUMAN-PAPILLOMAVIRUS E7 INHIBITS UNSCHEDULED DNA-SYNTHESIS REACTIVATED IN DIFFERENTIATED KERATINOCYTES

Productive infection by human papillomaviruses (HPVs) occurs only in d ifferentiated squamous epithelial cells in papillomas, condylomata, an d low grade intraepithelial neoplasias, Host DNA replication is reacti vated in a fraction of terminally differentiated keratinocytes in beni gn human lesions and in organotypic raft cultures of primary human ker atinocytes (PHKs) transduced with retroviruses expressing HPV-18 E7 on cogene from its native upstream regulatory region (URR), Thus the natu ral function of E7 protein, which inactivates pRB family proteins, is to induce host genes essential to support viral DNA replication in pos t-mitotic cells, Using this raft culture model system, we show that HP V-18 URR-E7 induces the universal cyclin-dependent kinase inhibitor p2 1cip1 protein in a fraction of differentiated PHKs, Induction is media ted by posttranscriptional mechanisms independent of p53, Double immun ofluorescence studies demonstrate that, in raft cultures and in laryng eal papillomas, p21cip1 induction and reactivated host DIVA synthesis take place in a mutually exclusive manner in PCNA-positive, differenti ated keratinocytes, We suggest that p21cip1 induction effectively bloc ks unscheduled DNA synthesis reactivated by E7, These results begin to explain the inverse relationship between p21cip1 induction and HPV ac tivities previously observed in a spectrum of benign lesions regardles s of HPV types present.