A novel mechanism by which thiazolidinediones facilitate the proteasomal degradation of cyclin D1 in cancer cells

Shuo Wei, Hsiao Ching Yang, Hsiao Ching Chuang, Jian Yang, Samuel K. Kulp, Pei Jung Lu, Ming Derg Lai, Ching Shih Chen

研究成果: Article同行評審

61 引文 斯高帕斯(Scopus)

摘要

This study identifies a novel mechanism by which thiazolidinediones mediate cyclin D1 repression in prostate cancer cells. Based on the finding that the thiazolidinedione family of peroxisome proliferator-activated receptor γ (PPARγ) agonists mediated PPARγ-independent cyclinD1degradation, we developed a novel PPARγ-inactive troglitazone derivative, STG28, with high potency in cyclin D1 ablation. STG28-mediated cyclin D1 degradation was preceded by Thr-286 phosphorylation and nuclear export, which however, were independent of glycogen synthase kinase 3β. Mutational analysis further confirmed the pivotal role of Thr-286 phosphorylation in STG28-induced nuclear export and proteolysis. Of several kinases examined, inhibition of IκB kinase α blocked STG28-mediated cytoplasmic sequestration and degradation of cyclin D1. Pulldown of ectopically expressed Cul1, the scaffold protein of the Skp-Cullin-F-box E3 ligase, in STG28-treated cells revealed an increased association of cyclin D1 with β-TrCP, whereas no specific binding was noted with other F-box proteins examined, including Skp2, Fbw7, Fbx4, and Fbxw8. This finding represents the first evidence that cyclin D1 is targeted by β-TrCP. Moreover, β-TrCP expression was up-regulated in response to STG28, and ectopic expression and small interfering RNA-mediated knockdown of β-TrCP enhanced and protected against STG28-facilitated cyclin D1 degradation, respectively. Because cyclin D1 lacks theDSGdestruction motif, mutational and modeling analyses indicate that cyclin D1 was targeted by β-TrCP through an unconventional recognition site, 279EEVDLACpT286, reminiscent to that of Wee1. Moreover, we obtained evidence that this β-TrCP-dependent degradation takes part in controlling cyclin D1 turnover when cancer cells undergo glucose starvation, which endows physiological relevance to this novel mechanism.

原文English
頁(從 - 到)26759-26770
頁數12
期刊Journal of Biological Chemistry
283
發行號39
DOIs
出版狀態Published - 2008 九月 26

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子生物學
  • 細胞生物學

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