Wang Yunyuan V, Wade Mark, Wong Eetsin, Li Yao-Cheng, Rodewald Luo Wei, Wahl Geoffrey M
Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12365-70. doi: 10.1073/pnas.0701497104. Epub 2007 Jul 17.
P53 regulates numerous downstream targets to induce cell cycle arrest, senescence, apoptosis, and DNA repair in response to diverse stresses. Hdm2 and Hdmx are critical negative regulators of P53 because Hdm2 regulates P53 abundance, and both can antagonize P53 transactivation. Modest changes in Hdm2 or Hdmx abundance affect P53 regulation, yet quantitative information regarding their endogenous intracellular concentrations and subcellular distributions during a stress response are lacking. We analyzed these parameters in normal and cancer cells after DNA damage. Our data show that the nuclear abundance of Hdm2 and Hdmx relative to P53 limits P53 activity in cells growing in culture. Upon DNA damage, P53 nuclear abundance increases, whereas Hdm2 and Hdmx stability decreases, which greatly limits their ability to antagonize P53, regardless of their levels. These data indicate that the damage-activated switch in Hdm2 ubiquitin ligase preference from P53 to itself and Hdmx is central to P53 activation.
p53调节众多下游靶点，以响应各种应激诱导细胞周期停滞、衰老、凋亡和DNA修复。Hdm2和Hdmx是p53的关键负调节因子，因为Hdm2调节p53的丰度，且二者均可拮抗p53的反式激活。Hdm2或Hdmx丰度的适度变化会影响p53的调节，但缺乏关于它们在应激反应期间内源性细胞内浓度和亚细胞分布的定量信息。我们分析了DNA损伤后正常细胞和癌细胞中的这些参数。我们的数据表明，相对于p53，Hdm2和Hdmx的核丰度限制了培养中生长的细胞中p53的活性。DNA损伤后，p53的核丰度增加，而Hdm2和Hdmx的稳定性降低，这极大地限制了它们拮抗p53的能力，无论它们的水平如何。这些数据表明，Hdm2泛素连接酶偏好从p53转向自身和Hdmx的损伤激活开关是p53激活的核心。
