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- Title
ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2.
- Authors
Chang, D. L. F.; Qiu, W.; Ying, H.; Zhang, Y.; Chen, C.-Y.; Xiao, Z.-X. J.
- Abstract
The INK4a/ARF locus, encoding two tumor suppressor proteins, p16INK4a and p14ARF (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 p16INK4a is a critical component in retinoblastoma protein (Rb)-mediated growth regulatory pathway, p14ARF 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.Oncogene (2007) 26, 4627–4634; doi:10.1038/sj.onc.1210254; published online 5 February 2007
- Subjects
RETINOBLASTOMA; RETINA cancer; CANCER cells; CELL cycle; TUMOR proteins; TUMOR suppressor proteins
- Publication
Oncogene, 2007, Vol 26, Issue 32, p4627
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210254