p53 Plays a Key Role in Exporting Bid from the Nucleus to Induce Cell Death in Response to Etoposide Treatment

Appropriate subcellular localization of proteins is crucial for regulating their functions. Both p53 and the BH3-only Bid play roles in the development and the treatment of hepatocellular carcinoma. Bid genomic loci contain p53-binding DNA response elements and Bid can mediate p53-dependent transactivation. However, how these molecules function in the liver cells is not completely known. In this study, liver cells were stimulated by etoposide to damage DNA, and the location and the interaction of Bid and p53 were examined by Western blot, immonocchemical staining, immunoprecipitation and siRNA methods. Our data showed that etoposide-induced DNA damage significantly induced p53 and Bid nuclear export. When cells were stimulated by etoposide, p53 could, through the interaction with Bid, cause translocation of Bid from the nucleus to the cytoplasm and on to its ultimate location in the mitochondria. Moreover, p53 physically associated with Bid, and both p53 and Bid cooperatively promoted cell death induced by etoposide. Knockdown of Bid expression notably attenuated cell death induced by etoposide and also released p53 from the mitochondria. In conclusion, these findings reveal a novel mechanism how p53 facilitates Bid nuclear export and how both of them interact in the nucleus and the mitochondria to induce apoptosis in response to etoposide-induced DNA damage.

Keywords: Bid, cell death, etoposide, hepatocellular carcinoma, mitochondria, nucleus, p53.