IRIS publication 243939901
A novel CyclinE/CyclinA-CDK Inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: Implications in cancer therapy
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TY - JOUR - Dai, L,Liu, YQ,Liu, JY,Wen, XM,Xu, ZS,Wang, Z,Sun, H,Tang, SB,Maguire, AR,Quan, JM,Zhang, H,Ye, T - 2013 - June - Cancer Letters - A novel CyclinE/CyclinA-CDK Inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: Implications in cancer therapy - Validated - WOS: 43 () - p27(Kip1) CyclinE/CyclinA-CDK Inhibitor Cell cycle Proliferation Apoptosis DEPENDENT-KINASE INHIBITOR UBIQUITIN-MEDIATED DEGRADATION P27 PHOSPHORYLATION COMPLEX E-CDK2 CKS1 - 333 - 103 - 112 - 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. (C) 2013 Elsevier Ireland Ltd. All rights reserved. - 10.1016/j.canlet.2013.01.025 DA - 2013/06 ER -
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@article{V243939901, = {Dai, L and Liu, YQ and Liu, JY and Wen, XM and Xu, ZS and Wang, Z and Sun, H and Tang, SB and Maguire, AR and Quan, JM and Zhang, H and Ye, T }, = {2013}, = {June}, = {Cancer Letters}, = {A novel CyclinE/CyclinA-CDK Inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: Implications in cancer therapy}, = {Validated}, = {WOS: 43 ()}, = {p27(Kip1) CyclinE/CyclinA-CDK Inhibitor Cell cycle Proliferation Apoptosis DEPENDENT-KINASE INHIBITOR UBIQUITIN-MEDIATED DEGRADATION P27 PHOSPHORYLATION COMPLEX E-CDK2 CKS1}, = {333}, pages = {103--112}, = {{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. (C) 2013 Elsevier Ireland Ltd. All rights reserved.}}, = {10.1016/j.canlet.2013.01.025}, source = {IRIS} }
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AUTHORS | Dai, L,Liu, YQ,Liu, JY,Wen, XM,Xu, ZS,Wang, Z,Sun, H,Tang, SB,Maguire, AR,Quan, JM,Zhang, H,Ye, T | ||
YEAR | 2013 | ||
MONTH | June | ||
JOURNAL_CODE | Cancer Letters | ||
TITLE | A novel CyclinE/CyclinA-CDK Inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: Implications in cancer therapy | ||
STATUS | Validated | ||
TIMES_CITED | WOS: 43 () | ||
SEARCH_KEYWORD | p27(Kip1) CyclinE/CyclinA-CDK Inhibitor Cell cycle Proliferation Apoptosis DEPENDENT-KINASE INHIBITOR UBIQUITIN-MEDIATED DEGRADATION P27 PHOSPHORYLATION COMPLEX E-CDK2 CKS1 | ||
VOLUME | 333 | ||
ISSUE | |||
START_PAGE | 103 | ||
END_PAGE | 112 | ||
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. (C) 2013 Elsevier Ireland Ltd. All rights reserved. | ||
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DOI_LINK | 10.1016/j.canlet.2013.01.025 | ||
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