MDM2促进p21waf1/cip1的蛋白酶体周转，且不依赖于泛素化。
MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation.
作者信息
Jin Yetao, Lee Hunjoo, Zeng Shelya X, Dai Mu-Shui, Lu Hua
机构信息
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
出版信息
EMBO J. 2003 Dec 1;22(23):6365-77. doi: 10.1093/emboj/cdg600.
The CDK inhibitor p21waf1/cip1 is degraded by a ubiquitin-independent proteolytic pathway. Here, we show that MDM2 mediates this degradation process. Overexpression of wild-type or ring finger-deleted, but not nuclear localization signal (NLS)-deleted, MDM2 decreased p21waf1/cip1 levels without ubiquitylating this protein and affecting its mRNA level in p53(-/-) cells. This decrease was reversed by the proteasome inhibitors MG132 and lactacystin, by p19(arf), and by small interfering RNA (siRNA) against MDM2. p21waf1/cip1 bound to MDM2 in vitro and in cells. The p21waf1/cip1-binding-defective mutant of MDM2 was unable to degrade p21waf1/cip1. MDM2 shortened the half-life of both exogenous and endogenous p21waf1/cip1 by 50% and led to the degradation of its lysine-free mutant. Consequently, MDM2 suppressed p21waf1/cip1-induced cell growth arrest of human p53(-/-) and p53(-/-)/Rb(-/-)cells. These results demonstrate that MDM2 directly inhibits p21waf1/cip1 function by reducing p21waf1/cip1 stability in a ubiquitin-independent fashion.
细胞周期蛋白依赖性激酶（CDK）抑制剂p21waf1/cip1通过一条不依赖泛素的蛋白水解途径被降解。在此，我们表明MDM2介导了这一降解过程。野生型或缺失环指结构但未缺失核定位信号（NLS）的MDM2过表达，可降低p21waf1/cip1水平，而不会使该蛋白泛素化，也不会影响其在p53基因敲除细胞中的mRNA水平。蛋白酶体抑制剂MG132和乳胞素、p19（arf）以及针对MDM2的小干扰RNA（siRNA）可逆转这种降低。p21waf1/cip1在体外和细胞中均与MDM2结合。MDM2的p21waf1/cip1结合缺陷型突变体无法降解p21waf1/cip1。MDM2使外源性和内源性p21waf1/cip1的半衰期缩短了50%，并导致其无赖氨酸突变体的降解。因此，MDM2抑制了p21waf1/cip1诱导的人p53基因敲除细胞和p53基因敲除/Rb基因敲除细胞的细胞生长停滞。这些结果表明，MDM2通过以不依赖泛素的方式降低p21waf1/cip1的稳定性，直接抑制p21waf1/cip1的功能。
Zotero 插件