Jascur Thomas, Brickner Howard, Salles-Passador Isabelle, Barbier Valerie, El Khissiin Abdelhamid, Smith Brian, Fotedar Rati, Fotedar Arun
Sidney Kimmel Cancer Center, 10835 Altman Road, San Diego, CA 92121, USA.
Mol Cell. 2005 Jan 21;17(2):237-49. doi: 10.1016/j.molcel.2004.11.049.
p21(WAF1/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.
p21（WAF1/CIP1）是一种细胞周期蛋白依赖性激酶抑制剂，也是细胞周期的关键调节因子，它受到p53依赖性和非依赖性机制的转录调控以及蛋白酶体的翻译后调控。我们鉴定出了WISp39，一种能与p21结合的四肽重复序列（TPR）蛋白。WISp39通过防止新合成的p21蛋白被蛋白酶体降解来使其稳定。WISp39、p21和hsp90在体内形成三聚体复合物。WISp39 C末端TPR结构域内的点突变消除了WISp39与Hsp90的相互作用。尽管这种WISp39 TPR突变体在体内能与p21结合，但它无法使p21稳定。我们的结果表明，WISp39招募Hsp90来调节p21蛋白的稳定性。通过小干扰RNA（siRNA）下调WISp39可阻止电离辐射后p21的积累和细胞周期停滞。这些结果证明了WISp39对p21蛋白进行翻译后稳定在调节细胞内p21活性中的重要性。
