Direct Control of Cell Cycle Gene Expression by Proto-Oncogene Product ACTR, and Its Autoregulation Underlies Its Transforming Activity

Abstract

ACTR (also called AIB1 and SRC-3) was identified as a coactivator for nuclear receptors and is linked to multiple types of human cancer due to its frequent overexpression. However, the molecular mechanism of ACTR oncogenicity and its function independent of nuclear receptors remain to be defined. We demonstrate here that ACTR is required for both normal and malignant human cells to effectively enter S phase. RNA interference-mediated depletion and chromatin immunoprecipitation assays show that endogenous ACTR directly controls the expression of genes important for initiation of DNA replication, which include cdc6, cdc25A, MCM7, cyclin E, and Cdk2. Moreover, consistent with its critical role in cell cycle control, ACTR expression appears to be cell cycle regulated, which involves E2F. Interestingly, ACTR is recruited to its own promoter at the G₁/S transition and activates its own expression, suggesting a positive feedback mechanism for ACTR action in the control of cell cycle progression and for its aberrant expression in cancers. Importantly, overexpression of ACTR alone transforms human mammary epithelial cells, which requires its association with E2F. These findings reveal a novel role for ACTR in cell cycle control and support the notion that the ability of aberrant ACTR to deregulate the cell cycle through E2F underlies its oncogenicity in human cancers.

We are grateful to J. Nevins, K. Helin, G. Leone, Y. Nakatani, and W. Lin for providing reagents. We thank H. Kung and R. Wisdom for constructive discussions. We appreciate the technical help from P. Mack, D. Hsu, and A. Rabinovich and the University of California at Davis Flow Cytometry Core Facility for FACS analysis.

This study was supported by grants from the National Institutes of Health (DK60019) and the California Breast Cancer Research Program and Cancer Research Coordinating Committee programs to H.W.C. M.C.L. was a trainee of an National Institutes of Health molecular and cellular biology training grant.