CDK inhibitors: positive and negative regulators of G1-phase progression
The accumulation of D cyclins will lead to two results: first, the phosphorylation of Rb by cyclin D-dependent kinases lead to its inactive. Second, in the G1 phase, CDK2 reinforces CDK4 to finish Rb phosphorylation and induces the destruction of P27 kip1.
If PI3K pathway is inhibited, cyclinD1 will be phosphorylated and transported into nuclear. The acceleration of degradation in cytoplasm will be shortening the half-life of CyclinD1. Coupled with the degradation of cyclin A in G2, cyclin E will be proteolysis. The negative regulators Rb and Cip/Kip proteins played crucial role in G1 phase. Hence, in G1 phase, cyclin D and mitogen reinstitute are required. Previously study showed that D-CDK complexes were inhibited by P27 kip1. However, the function of accelerating the activity of cyclin E -CDK2 is more effective. Both p21 and p27 accelerate cyclin D-CDK assembly by stabilizing the complexes in vitro test. p21 Cip1, stimulated the assembly of enzymatically active cyclin D-dependent kinases through entering into higher order complexes with cyclin D and CDK4. It is unnecessary for CDKs assembly with the interaction of p21 with CDKs.
The apoptosis was not detected in serum-starved transfected p27 –/– cells transfected with the p27 plasmid while detected in nontransfected cells.p27 mutant plasmid transfected cells does not bind CDK2 and GFP, also, no cell programmed death was detected. TUNEL method has been used during this study, the staining was detected in antisense oligonucleotides (to p27) transfected cells. WB analysis showed that,CDK2 activity was increased in p27-/- mesangial cells and p27-/- fibroblasts in contrast with p27+/+ cells. the activity of CDK2 was remained increase at 6h and 18h after growth factor deprivation in p27-/-cells compared with p27+/+ cells, and CDK2 remained on protein levels in this experiment. Quantitation of CDK2 kinase activity was detected. In p27 –/– and p27 +/+ cells, cyclin E–CDK2 and cyclin A–CDK2 activity were increased. However, in p27 –/– mesangial cells, cyclin A–CDK2 activity, but not cyclinE–CDK2 activity, remained increased after growth factor deprivation. All in all, this study suggested that p27 has two biological functions, preventing cell death and accelerating proliferation. The function of p27 was different under certain condition.
Related references:
Charles J. Sherr and James M. Roberts,CDK inhibitors: positive and negative regulators of G1-phase progression,Genes Dev. 1999 13: 1501-1512
Related posts:
Modulation of apoptosis by the cyclin-dependent Crizotinib and PF-2341066.
If PI3K pathway is inhibited, cyclinD1 will be phosphorylated and transported into nuclear. The acceleration of degradation in cytoplasm will be shortening the half-life of CyclinD1. Coupled with the degradation of cyclin A in G2, cyclin E will be proteolysis. The negative regulators Rb and Cip/Kip proteins played crucial role in G1 phase. Hence, in G1 phase, cyclin D and mitogen reinstitute are required. Previously study showed that D-CDK complexes were inhibited by P27 kip1. However, the function of accelerating the activity of cyclin E -CDK2 is more effective. Both p21 and p27 accelerate cyclin D-CDK assembly by stabilizing the complexes in vitro test. p21 Cip1, stimulated the assembly of enzymatically active cyclin D-dependent kinases through entering into higher order complexes with cyclin D and CDK4. It is unnecessary for CDKs assembly with the interaction of p21 with CDKs.
The apoptosis was not detected in serum-starved transfected p27 –/– cells transfected with the p27 plasmid while detected in nontransfected cells.p27 mutant plasmid transfected cells does not bind CDK2 and GFP, also, no cell programmed death was detected. TUNEL method has been used during this study, the staining was detected in antisense oligonucleotides (to p27) transfected cells. WB analysis showed that,CDK2 activity was increased in p27-/- mesangial cells and p27-/- fibroblasts in contrast with p27+/+ cells. the activity of CDK2 was remained increase at 6h and 18h after growth factor deprivation in p27-/-cells compared with p27+/+ cells, and CDK2 remained on protein levels in this experiment. Quantitation of CDK2 kinase activity was detected. In p27 –/– and p27 +/+ cells, cyclin E–CDK2 and cyclin A–CDK2 activity were increased. However, in p27 –/– mesangial cells, cyclin A–CDK2 activity, but not cyclinE–CDK2 activity, remained increased after growth factor deprivation. All in all, this study suggested that p27 has two biological functions, preventing cell death and accelerating proliferation. The function of p27 was different under certain condition.
Related references:
Charles J. Sherr and James M. Roberts,CDK inhibitors: positive and negative regulators of G1-phase progression,Genes Dev. 1999 13: 1501-1512
Related posts:
Modulation of apoptosis by the cyclin-dependent Crizotinib and PF-2341066.
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