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Department of Physiology, Graduate School of Medicine and Dentistry, Okayama University, Okayama 700-8558 [T. T., K. T., M. M., S-T. L., A. M., H. M.]; Department of Oral and Maxillofacial Surgery, Kobe City General Hospital, Kobe 650-0046 [T. T.]; and "Protein Therapy," Preventure Program, and Japan Science and Technology Corporation, Okayama 700-8558 [Y-F. L., H. M.], Japan

Recent studies suggest that several proteins can transverse biological membranes through protein transduction. The protein transduction domains of these proteins, 10–16 residues long, have been identified as critical domains for the protein transduction. Poly-arginine peptide also has the ability of protein transduction. Here, we show that the protein delivery system using 11 poly-arginine peptides (11R) is a powerful tool for the transduction of the biologically active tumor suppressor protein, p53, to suppress the proliferation of oral cancer cells. The 11R-fused p53 proteins (11R-p53) effectively penetrated across the plasma membrane of the cancer cells and translocated into the nucleus. The proteins induced the activity of the p21/WAF promoter and inhibited the proliferation of human oral cancer cells, in which the p53 gene was mutated. The effect was equivalent to that of the adenovirus-mediated p53 gene transduction system. Moreover, 11R-p53 enhanced the cisplatin-dependent induction of apoptosis of the cells. These data suggest that this protein transduction method may become a promising cancer therapy.

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