Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/29141
Title: A novel CyclinE/CyclinA-CDK Inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival : implications in cancer therapy
Authors: Dai, L
Liu, Y
Liu, J
Wen, X
Xu, Z
Wang, Z
Sun, H
Tang, S
Maguire, AR
Quan, J
Zhang, H
Ye, T 
Keywords: P27(Kip1)
CyclinE/CyclinA-CDK Inhibitor
Cell cycle
Proliferation
Apoptosis
Issue Date: 2013
Publisher: Elsevier Ireland Ltd
Source: Cancer letters, 2013, v. 333, no. 1, p. 103-112 How to cite?
Journal: Cancer Letters 
Abstract: p27(Kip1) (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 p21(Cip1/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.
URI: http://hdl.handle.net/10397/29141
ISSN: 0304-3835
DOI: 10.1016/j.canlet.2013.01.025
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