Zhang Zhuo, Zhang Ruiwen
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
EMBO J. 2008 Mar 19;27(6):852-64. doi: 10.1038/emboj.2008.25. Epub 2008 Feb 28.
Downregulation of p53 by MDM2-mediated proteasomal degradation makes cells resistant to apoptosis. The MDM2-p53 interaction is well characterized, but the mechanisms that regulate the interaction are not well understood. Here, we show that PA28gamma, a proteasome activator that inhibits apoptosis and promotes cell cycle progression through unknown mechanisms, exerts an effect as a cofactor in the MDM2-p53 interaction. The polymer form of PA28gamma interacts with both MDM2 and p53 proteins and facilitates their physical interaction. This promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. Elimination of endogenous PA28gamma in human cancer cells abrogates MDM2-mediated p53 degradation, increases the activity of p53, and enhances apoptosis. These findings reveal the mechanism by which PA28gamma affects apoptosis and proliferation. Manipulation of the level of PA28gamma, an approach that would regulate the cellular content of p53, may improve the efficacy of current cancer therapies.
MDM2介导的蛋白酶体降解导致p53下调，使细胞对凋亡产生抗性。MDM2与p53之间的相互作用已得到充分表征，但其调控机制尚不清楚。在此，我们表明PA28γ作为一种蛋白酶体激活剂，通过未知机制抑制凋亡并促进细胞周期进程，在MDM2与p53的相互作用中作为辅助因子发挥作用。PA28γ的聚合物形式与MDM2和p53蛋白均相互作用，并促进它们的物理相互作用。这促进了p53的泛素化及MDM2依赖的蛋白酶体降解，限制了其积累，并导致DNA损伤后凋亡受到抑制。消除人类癌细胞中的内源性PA28γ可消除MDM2介导的p53降解，增加p53的活性，并增强凋亡。这些发现揭示了PA28γ影响凋亡和增殖的机制。操纵PA28γ的水平，一种可调节p53细胞含量的方法，可能会提高当前癌症治疗的疗效。
