1. ¹Graduate Program in Molecular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
2. ²Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
3. ³The Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
4. ⁴Department of Pathology, Boston University School of Medicine, Boston, MA, USA

Correspondence: Dr Z-XJ Xiao, Department of Biochemistry, Boston University School of Medicine, 715 Albany St., K-423, Boston, MA 02118, USA. E-mail: jxiao@bu.edu

Received 5 June 2006; Revised 30 November 2006; Accepted 4 December 2006; Published online 5 February 2007.

Abstract

The INK4a/ARF locus, encoding two tumor suppressor proteins, p16^INK4a and p14^ARF (ARF), plays key roles in many cellular processes including cell proliferation, apoptosis, cellular senescence and differentiation. Inactivation of INK4a/ARF is one of the most frequent events during human cancer development. Although p16^INK4a is a critical component in retinoblastoma protein (Rb)-mediated growth regulatory pathway, p14^ARF plays a pivotal role in the activation of p53 upon oncogenic stress signals. A body of evidence indicates that ARF also possesses growth suppression functions independent of p53, the mechanism of which is not well understood. We have recently shown that MDM2 interacts with Rb and promotes proteasome-dependent Rb degradation. In this study, we show that ARF disrupts MDM2–Rb interaction resulting in Rb accumulation. Wild-type ARF, but not ARF mutant defective in MDM2 interaction, stabilizes Rb and inhibits colony foci formation independent of p53. In addition, ablation of Rb impairs ARF function in growth suppression. Thus, this study demonstrates that ARF plays a direct role in regulation of Rb and suggests that inactivation of ARF may lead to defects in both p53 and Rb pathways in human cancer development.