Regulation of p21WAF1/CIP1 stability by WISp39, a Hsp90 binding TPR protein
Regulation of p21WAF1/CIP1 stability by WISp39, a Hsp90 binding TPR protein
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DOI：
10.1016/j.molcel.2004.11.049
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发表时间：
2005-01-21
期刊：
影响因子：
16
通讯作者：
Fotedar, A
中科院分区：
文献类型：
--
作者：
Jascur, T;Brickner, H;Fotedar, A
p21（WAH/CIP 1）是一种细胞周期蛋白依赖性激酶抑制剂，是细胞周期的重要调控因子，在转录水平上受p53依赖和非依赖机制的调控，在转录后水平上受蛋白酶体的调控。我们已经鉴定了WISp 39，一种结合p21的tetratricopeptide repeat（TPR）蛋白。WISp 39通过阻止其蛋白酶体降解来稳定新合成的p21蛋白。WISp 39、p21和hsp 90在体内形成三聚体复合物。WISp 39与Hsp 90的相互作用通过WISp 39的C-末端TPR结构域内的点突变而消除。虽然这种WISp 39 TPR突变体在体内结合p21，但它不能稳定p21。我们的研究结果表明，WISp 39招募热休克蛋白90调节p21蛋白的稳定性。siRNA下调WISp 39可防止电离辐射后p21的积累和细胞周期停滞。结果表明WISp 39对p21蛋白的翻译后稳定在调节细胞p21活性中的重要性。
p21(WAH/CIP1), a cyclin-dependent kinase inhibitor and a critical regulator of cell cycle, is controlled transcriptionally by p53-dependent and -independent mechanisms and posttranslationally by the proteasome. We have identified WISp39, a tetratricopeptide repeat (TPR) protein that binds p21. WISp39 stabilizes newly synthesized p21 protein by preventing its proteasomal degradation. WISp39, p21, and hsp90 form a trimeric complex in vivo. The interaction of WISp39 with Hsp90 is abolished by point mutations within the C-terminal TPR domain of WISp39. Although this WISp39 TPR mutant binds p21 in vivo, it fails to stabilize p21. Our results suggest that WISp39 recruits Hsp90 to regulate p21 protein stability. WISp39 downregulation by siRNA prevents the accumulation of p21 and cell cycle arrest after ionizing radiation. The results demonstrate the importance of posttranslational stabilization of p21 protein by WISp39 in regulating cellular p21 activity.