Cell cycle regulation of the nuclear receptor coactivator SRC-3AIB1 and impact of overexpression

Abstract

SRC-3 is a nuclear receptor coactivator which is amplified and overexpressed in many breast cancers. Although the importance of this protein in a plethora of cellular functions has been established, little is understood about how it is regulated. In this study, we have investigated the regulation of SRC-3 throughout the cell cycle and the effects of aberrant SRC-3 expression. We have found that SRC-3 is regulated throughout the cell cycle via changes in compartmentalization, post-translational modification and degradation, in a Cdk1-, MAPK- and proteasome-dependent manner. Deregulation of SRC-3 expression has substantial effects on cellular growth rate, cell cycle progression, cell morphology and DNA content. Collectively, these findings suggest that disruption of SRC-3 activity gives rise to cells with aberrant cell cycles, resulting in genetic instability and potential aneuploidy. Although in most cells this disruption results in cell cycle arrest and possible apoptosis, it might also set the stage for SRC-3-mediated oncogenesis.