BACKGROUND: To clarify the roles of the p53-MDM2-p14ARF cell cycle regulation system in oncogenesis and cytodifferentiation of odontogenic tumors, p53 gene status and expression of p53, MDM2, and p14ARF proteins was analyzed in ameloblastomas as well as tooth germs. METHODS: Paraffin sections of 16 tooth germs and 46 benign and 5 malignant ameloblastomas were examined immunohistochemically for the expression of p53, MDM2, and p14ARF proteins. Frozen tissue samples of 10 benign ameloblastomas and 1 malignant (metastasizing) ameloblastoma were analyzed by direct DNA sequencing to detect p53 gene alteration. RESULTS: Immunohistochemical reactivity for p53 was detected in 2 of 13 tooth germs, 13 of 29 ameloblastomas, and 5 of 5 malignant ameloblastomas, and the expression ratio of p53 in tooth germs was significantly lower than those in benign and malignant ameloblastomas. Direct DNA sequencing showed no alteration of p53 gene exons 5-8 in any sample of 10 benign ameloblastomas and 1 metastasizing ameloblastoma. Expression of MDM2 and p14ARF was detected in all samples of normal and neoplastic odontogenic epithelium, and the expression ratios in tooth germs tended to be lower than those in benign and malignant ameloblastomas. In ameloblastomas, expression of p53, MDM2, and p14 ARF was significantly higher in plexiform cases than in follicular cases. Markedly decreased reactivity for p53, MDM2, and p14ARF was detected in keratinizing and granular cells in ameloblastoma subtypes. Basal cell ameloblastoma showed slightly higher reactivity for p53, MDM2, and p14 ARF as compared with other subtypes. CONCLUSION: Elevated expression of p53, MDM2, and p14ARF in benign and malignant ameloblastomas suggests that alteration of the p53-MDM2-p14ARF cascade is involved in oncogenesis and/of malignant transformation of odontogenic epithelium. p53 gene status implied that p53 mutation might play a minor role in neoplastic changes of odontogenic epithelium. Immunoreactivity for p53, MDM2, and p14 ARF in ameloblastoma variants suggests that these factors might be associated with tissue structuring and cytodifferentiation of ameloblastomas.