Chi Xin-Zi, Kim Jiyeon, Lee Yong-Hee, Lee Jung-Won, Lee Kyeong-Sook, Wee Heejun, Kim Wun-Jae, Park Woo-Yoon, Oh Byung-Chul, Stein Gary S, Ito Yoshiaki, van Wijnen Andre J, Bae Suk-Chul
Departments of Biochemistry, College of Medicine, Institute of Tumor Research, Chungbuk National University, Cheongju, South Korea.
Cancer Res. 2009 Oct 15;69(20):8111-9. doi: 10.1158/0008-5472.CAN-09-1057. Epub 2009 Oct 6.
The p14(ARF)-MDM2-p53 pathway constitutes an effective mechanism for protecting cells from oncogenic stimuli such as activated Ras and Myc. Importantly, Ras activation induces p14(ARF) and often occurs earlier than p53 inactivation during cancer development. Here, we show that RUNX3, a tumor suppressor in various tumors including stomach, bladder, colon, and lung, is stabilized by Ras activation through the p14(ARF)-MDM2 signaling pathway. RUNX3 directly binds MDM2 through its Runt-related DNA-binding domain. MDM2 blocks RUNX3 transcriptional activity by interacting with RUNX3 through an acidic domain adjacent to the p53-binding domain of MDM2 and ubiquitinates RUNX3 on key lysine residues to mediate nuclear export and proteasomal degradation. Our data indicate that the lineage-specific tumor suppressor RUNX3 and the ubiquitous p53 protein are both principal responders of the p14(ARF)-MDM2 cell surveillance pathway that prevents pathologic consequences of abnormal oncogene activation.
p14(ARF)-MDM2-p53信号通路构成了一种有效的机制，可保护细胞免受致癌刺激，如活化的Ras和Myc。重要的是，Ras激活会诱导p14(ARF)，并且在癌症发展过程中通常比p53失活更早发生。在此，我们表明RUNX3作为包括胃、膀胱、结肠和肺在内的多种肿瘤中的肿瘤抑制因子，通过p14(ARF)-MDM2信号通路被Ras激活所稳定。RUNX3通过其Runt相关的DNA结合结构域直接结合MDM2。MDM2通过与RUNX3相互作用，通过MDM2的p53结合结构域附近的酸性结构域来阻断RUNX3的转录活性，并在关键赖氨酸残基上使RUNX3泛素化，以介导核输出和蛋白酶体降解。我们的数据表明，谱系特异性肿瘤抑制因子RUNX3和普遍存在的p53蛋白都是p14(ARF)-MDM2细胞监测通路的主要应答者，该通路可预防异常癌基因激活的病理后果。
