P2-02-08: Int6 Regulates Both Proteasomal Degradation and Translation Initiation and Is Critical for Proper Formation of Acini by Human Mammary Epithelium.

Abstract

Abstract The mammalian INT6/EIF3E gene has been implicated in breast tumor formation, but its functional activities remain poorly defined. Consistent with the fact that Int6 is frequently down-regulated in human breast tumors, we found that repressing INT6 expression induced transformed properties in normal human mammary epithelial cells (MCF10A) in both 2D and 3D cultures. Int6 contains a PCI domain, found in several components of both the proteasome and the translation initiation factor eIF3, suggesting that it can functionally interact with both. Indeed, our data show that Int6 associates with proteasomes in human cells, and that INT6 knockdown prevents proper assembly of active proteasomes. In addition, we show that down-regulation of INT6 reduces translation initiation (both polysome formation and global protein synthesis). However, Int6 regulates translation selectively, reducing translation from cap-dependent and Bcl2- IRES reporters, but stimulating translation from the CVB3 IRES. These data collectively suggest that Int6 controls both protein synthesis and protein degradation, and is thus capable of fine-tuning protein levels. Abnormal levels of regulatory proteins caused by Int6 abnormalities may thus be responsible for disrupting normal morphogenesis of mammary epithelial cells and causing transformed phenotypes. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-02-08.