Apoptosis factor EI24/ PIG8 is a novel endoplasmic reticulum-localized Bcl-2-binding protein which is associated with suppression of breast cancer invasiveness.
p53 is a critical tumor suppressor which removes cells with DNA damage by regulating expression and activity of a select group of p53-induced genes (PIG) that subsequently induce apoptosis. PIG8 was also identified as a gene induced by etoposide and named etoposide-induced gene 24 (EI24). Later experiments established EI24/ PIG8 as a proapoptotic factor and suggested that it may function as a tumor suppressor. Indeed, EI24/ PIG8 is relatively highly mutated in aggressive breast cancers and is located in a region which expresses frequent loss of heterozygosity. However, despite these important observations, the activity and role of EI24/ PIG8 remain largely unknown. We used (immmuno)fluorescence microscopy and subcellular fractionation techniques to show that EI24/ PIG8 is localized in the endoplasmic reticulum (ER). Pull-down experiments showed that it specifically binds with Bcl-2, a death regulator known to reside in mitochondria, ER, and the nuclear envelope. EI24/PIG8-Bcl-2 binding was corroborated by coimmunoprecipitation and other in vitro and in vivo protein-protein binding assays. Further analysis showed that EI24/ PIG8 uses its N-terminal region to bind the BH3 domain in Bcl-2. Finally, we used immunohistochemical techniques to analyze expression of EI24/ PIG8 in breast cancer tissue progression arrays and showed that loss of EI24/ PIG8 is associated with tumor invasiveness but not with the development of the primary tumor. These results suggest that EI24/ PIG8 is a novel, ER-localized Bcl-2-binding protein which may contribute to apoptosis by modulating the activity and/or function of Bcl-2 in this organelle. EI24/ PIG8 may serve to prevent tumor spreading, consistent with its suspected role as a tumor suppressor.[1]References
- Apoptosis factor EI24/PIG8 is a novel endoplasmic reticulum-localized Bcl-2-binding protein which is associated with suppression of breast cancer invasiveness. Zhao, X., Ayer, R.E., Davis, S.L., Ames, S.J., Florence, B., Torchinsky, C., Liou, J.S., Shen, L., Spanjaard, R.A. Cancer Res. (2005) [Pubmed]
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