In the present study, we clarified that transforming growth factor beta (TGF-beta) induces cellular senescence in human normal diploid cells, TIG-1, and identified protein kinase Cs (PKCs) as downstream mediators of TGF-beta-induced cellular senescence. Among PKCs, we showed that PKC-delta induced cellular senescence in TIG-1 cells and was activated in replicatively and prematurely senescent TIG-1 cells. The causative role of PKC-delta in cellular senescence programs was demonstrated using a kinase negative PKC-delta and small interfering RNA against PKC-delta. Furthermore, PKC-delta was shown to function in human telomerase reverse transcriptase (hTERT) gene repression. These results indicate that PKC-delta plays a key role in cellular senescence programs, and suggest that the induction of senescence and hTERT repression are coordinately regulated by PKC-delta.
We constructed a novel cancer-specific regulatable adenoviral expression system comprising two vectors: one expressing rtTA, a reverse tetracycline transactivator regulated by the human telomerase reverse transcriptase (hTERT) gene promoter, the other expressing the target gene regulated by the tetracycline response element (TRE). rtTA transactivates target gene expression in the presence of doxycycline. Using these vectors, we constructed an adenoviral expression system, the Tel-On system, which enables highly efficient target gene transduction. This system enabled efficient and regulatable cancer-specific gene expression, and can be used in targeted cancer gene therapy.
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