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Our lab has shown that nucleolin, a multifunctional nucleolar protein binds to the 5’ untranslated region (UTR) of human p53 mRNA and suppresses its translation and its induction after DNA damage. Knock down of nucleolin enhances p53 translation while overexpressed nucleolin, together with Ras, transforms rat embryonic fibroblast (Takagi M et al Cell 123:1-15). In order to exclusively explore the molecular mechanism of this translational regulation of p53 by nucleolin, we utilized an in vitro transcription/translation system. In this system, we identified two independent cis elements involved in the repression of p53 translation: one in p53 5’UTR and the other in p53 coding sequence. And both cis elements require the presence of the 3’UTR of human p53 mRNA for repression. A computerized model suggests that a secondary structure formed by p53 5’UTR and 3’UTR may be crucial in attracting translational repressor (nucleolin for example) and/or blocking the access of the general translational machinery to human p53 mRNA. In addition, we also mapped the functional domains of nucleolin that regulates p53 translation. Surprisingly, two different domains of nucleolin: N-terminal domain and the RNA binding domain participate in p53 repression and p53 mRNA binding respectively. All these data help to elucidate the potential regulatory mechanism of human p53 translation by nucleolin and suggest an important role of nucleolin in regulating p53 dependent stress responses.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA