ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2
ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2
复制标题
DOI：
10.1038/sj.onc.1210254
复制
发表时间：
2007-07-12
期刊：
影响因子：
8
通讯作者：
Xiao, Z-X J.
中科院分区：
文献类型：
--
作者：
Chang, D. L. F.;Qiu, W.;Xiao, Z-X J.
INK4a/ARF基因编码两种肿瘤抑制蛋白p16(INK4a)和p14(ARF)(ARF)，在细胞增殖、凋亡、衰老和分化等多种细胞过程中发挥关键作用。INK4a/ARF失活是人类癌症发展过程中最常见的事件之一。虽然p16(INK4a)是视网膜母细胞瘤蛋白(Rb)介导的生长调节通路中的关键成分，但p14ARF在P53在致癌应激信号的激活中起着关键作用。大量证据表明，ARF还具有不依赖于P53的生长抑制功能，其作用机制尚不清楚。我们最近发现MDM2与Rb相互作用，并促进蛋白酶体依赖的Rb的降解。在本研究中，我们表明ARF破坏了MDM2-Rb的相互作用，导致Rb的积累。野生型ARF，而不是MDM2相互作用缺陷的ARF突变体，稳定Rb并抑制不依赖于P53的集落形成。此外，Rb的消融还削弱了ARF抑制生长的功能。因此，本研究证明ARF在Rb的调控中起直接作用，并提示ARF的失活可能导致人类癌症发生过程中P53和Rb通路的缺陷。
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, 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.