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: 27 ()
  - 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  - 
@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: 27 ()},
   = {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}
}
AUTHORSDai, L,Liu, YQ,Liu, JY,Wen, XM,Xu, ZS,Wang, Z,Sun, H,Tang, SB,Maguire, AR,Quan, JM,Zhang, H,Ye, T
YEAR2013
MONTHJune
JOURNAL_CODECancer Letters
TITLEA novel CyclinE/CyclinA-CDK Inhibitor targets p27(Kip1) degradation, cell cycle progression and cell survival: Implications in cancer therapy
STATUSValidated
TIMES_CITEDWOS: 27 ()
SEARCH_KEYWORDp27(Kip1) CyclinE/CyclinA-CDK Inhibitor Cell cycle Proliferation Apoptosis DEPENDENT-KINASE INHIBITOR UBIQUITIN-MEDIATED DEGRADATION P27 PHOSPHORYLATION COMPLEX E-CDK2 CKS1
VOLUME333
ISSUE
START_PAGE103
END_PAGE112
ABSTRACTp27(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_LINK10.1016/j.canlet.2013.01.025
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