Regulation of the Activity of AIB1, an Estrogen Coactivator, by Growth Factor Signals

摘要

AIB1 is a member of a coactivator family that potentiates the transcriptional activity of nuclear hormone receptors. The AIB1 gene is amplified in certain breast and ovarian cancers. AIB1 amplification is preferentially found in ER and progesterone receptor-positive breast cancers. These findings suggest that AIB1 plays a causative role in breast cancer development. Our lab recently identified AIB1 as a target of the MAPK signaling pathway (Font de Mora and Brown, Mol Cell Biol 20:5041, 2000). This signaling pathway is triggered by growth factors of the insulin-like growth factor (IGF) and epidermal growth factor (EGF) family. These growth factors and their receptors have also been implicated in the development and progression of breast tumors. Based on these findings, we propose that the phosphorylation of AIB1 by MAPK may represent part of the molecular mechanism that integrates signals from steroid hormones and growth factors. Furthermore, we hypothesize that AIB1 phosphorylation may contribute to the role that AIB1 plays in the development of breast cancer. In order to identify the sites of AIB1 that are phosphorylated by MAPK, seven potential MAPK phosphorylation sites were targeted for deletion and mutations. In vitro phosphorylation of the point mutations and internal deletions by Erk2 revealed 4 major sites of phosphorylation. In the future we plan to test these mutants for their ability to function as coactivators. Our study will help to understand how AIB1 activity is modulated by MAPK. This may help to determine how AIB1 is involved in the development of breast cancer.