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The high‐risk human papillomavirus E6 proteins have been shown to interact with and lead to degradation of  PDZ ‐domain‐containing proteins through its carboxy‐terminal motif. This  PDZ ‐binding motif plays important roles in transformation of cultured cells and carcinogenesis of E6‐transgenic mice. However, its biological effects on the natural host cells have not been elucidated. We have examined its roles in an  in vitro  carcinogenesis model for cervical cancer, in which E6 and E7 together with activated  HRAS  ( HRAS G   12V ) can induce tumorigenic transformation of normal human cervical keratinocytes. In this model, E6Δ151 mutant, which is defective in binding to  PDZ  domains, almost lost tumorigenic ability, whereas E6 SAT  mutant, which is defective in p53 degradation showed activity close to wild‐type E6. Interestingly, we found decreased expression of  PAR 3 in E6‐expressing cells independently of E6 AP , which has not been previously recognized. Therefore, we knocked down several  PDZ ‐domain containing proteins including  PAR 3 in human cervical keratinocytes expressing E7,  HRAS G   12V  and E6Δ151 to examine whether depletion of these proteins can restore the tumorigenic ability. Single knockdown of  SCRIB ,  MAGI 1 or  PAR 3 significantly but partially restored the tumorigenic ability. The combinatorial knockdown of  SCRIB  and  MAGI 1 cooperatively restored the tumorigenic ability, and additional depletion of  PAR 3 further enhanced the tumorigenic ability surpassing that induced by wild‐type E6. These data highlight the importance of the carboxy‐terminal motif of the E6 protein and downregulation of  PAR 3 in tumorigenic transformation of human cervical keratinocytes.

Roles of the PDZ ‐binding motif of HPV 16 E6 protein in oncogenic transformation of human cervical keratinocytes