期刊
CELL CYCLE
卷 13, 期 18, 页码 2879-2888出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/15384101.2014.946841
关键词
CDK4; CDK6; cell cycle-based tumor therapeutics; cyclin D3; p21; Palbociclib; PD0332991
类别
资金
- WELBIO (Walloon Excellence in Lifesciences and Biotechnology)
- Belgian Foundation against Cancer [2010-172]
- Belgian Fund for Scientific Medical Research (FRSM)
- National Fund for Scientific Research (FRS-FNRS, Belgium)
- Televie
- Docteur J.P. Naets Fund
CDK4 and CDK6 bound to D-type cyclins are master integrators of G1 phase cell cycle regulations by initiating the inactivating phosphorylation of the central oncosuppressor pRb. Because of their frequent deregulation in cancer, cyclin D-CDK4/6 complexes are emerging as especially promising therapeutic targets. The specific CDK4/6 inhibitor PD0332991 is currently tested in a growing number of phase II/III clinical trials against a variety of pRb-proficient chemotherapy-resistant cancers. We have previously shown that PD0332991 inhibits not only CDK4/6 activity but also the activation by phosphorylation of the bulk of cyclin D-CDK4 complexes stabilized by p21 binding. Here we show that PD0332991 has either a positive or a negative impact on the activation of cyclin D-CDK4/6 complexes, depending on their binding to p21. Indeed, whereas PD0332991 inhibits the phosphorylation and activity of p21-bound CDK4/6, it specifically stabilized activated cyclin D3-CDK4/6 complexes devoid of p21 and p27. After elimination of PD0332991, these activated cyclin D3-CDK4/6 complexes persisted for at least 24h, resulting in paradoxical cell cycle entry in the absence of a mitogenic stimulation. This unsuspected positive effect of PD0332991 on cyclin D3-CDK4/6 activation should be carefully assessed in the clinical evaluation of PD0332991, which until now only involves discontinuous administration protocols.
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