Transcription Factor NFAT1 Activates the mdm2 Oncogene Independent of p53

Although the MDM2-p53 interaction has been well documented, MDM2 overexpression is observed in human cancers with little or no functional p53, suggesting that mdm2 expression is regulated by mechanisms independent of p53. Dysregulation of NFAT signaling is associated with malignant transformation and cancer development and progression. In this study, we demonstrate that the human mdm2 P2 promoter contains a consensus binding site for the NFAT1 transcription factor. NFAT1 directly binds the mdm2 P2 promoter in vitro and in vivo, resulting in the up-regulation of mdm2 transcription. Enforced expression of NFAT1 results in an elevated MDM2 protein level and reduces p53 activation and function in response to DNA damage. Both NFAT1 and MDM2 are highly expressed in human hepatocellular carcinoma tissues, compared with adjacent normal liver tissues. There is a positive correlation between the NFAT1 and MDM2 levels in tumor tissues. The novel function of NFAT1 in the control of MDM2 expression provides a basis for future investigations of the role of NFAT1 in cancer development, progression, and therapy.