کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2113038 1084436 2013 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A novel CyclinE/CyclinA-CDK Inhibitor targets p27Kip1 degradation, cell cycle progression and cell survival: Implications in cancer therapy
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
A novel CyclinE/CyclinA-CDK Inhibitor targets p27Kip1 degradation, cell cycle progression and cell survival: Implications in cancer therapy
چکیده انگلیسی

p27Kip1 (p27) binds and inhibits the cyclin E- or cyclin A-associated cyclin-dependent kinases (CDKs)2 and other CDKs, and negatively regulates G1–G2 cell cycle progression. To develop specific CDK inhibitors, we have modeled the interaction between p27 and cyclin A-CDK2, and designed a novel compound that mimics p27 binding to cyclin A-CDK2. The chemically synthesized inhibitor exhibited high potency and selective inhibition towards cyclin E/cyclin A-CDK2 kinase in vitro but not other kinases. To facilitate permeability of the inhibitor, a cell penetrating peptide (CPP) was conjugated to the inhibitor to examine its effect in several cancer cell lines. The CPP-conjugated inhibitor significantly inhibited the proliferation of cancer cells. The treatment of the inhibitor resulted in the increased accumulation of p27 and p21Cip1/Waf1 (p21) and hypo-phosphorylation of retinoblastoma protein (Rb). The degradation of p27, mediated through the phosphorylation of threonine-187 in p27, was also inhibited. Consequently, exposure of cells to the inhibitor caused cell cycle arrest and apoptosis. We conclude that specific cyclinE/cyclin A-CDK2 inhibitors can be developed based on the interaction between p27 and cyclin/CDK to block cell cycle progression to prevent tumor growth and survival.


► Novel small molecules have been designed and synthesized to inhibit Cyclin E/Cyclin A-CDK kinase.
► The inhibitor targets p27Kip1 degradation.
► The inhibitor is not ATP analogues.
► The inhibitor only inhibits Cyclin E/Cyclin A-CDK but not other kinases.
► The inhibitor inhibits cancer cell proliferation and induces cell cycle arrest.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cancer Letters - Volume 333, Issue 1, 1 June 2013, Pages 103–112
نویسندگان
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