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. Mounts of evidence shows that cyclin-dependent kinase (CDK) inhibitors of the Cip/Kip family, including p57Kip2 and p27Kip1, regulate not only cell cycle exit but also the corticogenesis. However, the activities of p57Kip2 protein are poorly identified . In cell culture and vivo, Anna Tury.et al find p57Kip2 over expresses at E14.5â€15.5 elicite cell cycle exit, promote the transition from proliferation to neuronal differentiation, and enhance the process outgrowth, while opposite effects happen in precursors which is inadequate of p57Kip2.Later research show the overexpression of p57Kip2 stimulates precocious glial differentiation, exhibiting stage dependent effects. In embryonic cortex, p57Kip2 over-expression, promotes cell migration and changes in postnatal radial layer positioning. Although the two CKIs, both p57Kip2 and p27Kip1 take part in the induction of differentiation, p57Kip2 have twice effective in induction of neuronal differentiation as p27Kip1 and intolerant of astrogliogenic effect of ciliary neurotrophic factor, showing that, CKIs difference in regulation of cell fate decisions. At the molecular level, although the highly conserved N - terminal region drives the cell cycle withdrawal and differentiation, , C - terminal region of the p57Kip2 alone inhibits the migration. In addition, the effect of neurogenesis and gliogenesis of p57Kip2 requires N - terminal cyclin / CDK binding / inhibitory areas, while the previous study shows p27Kip1 cell cycle-independent functions. These research suggest p57Kip2 coordinates multiple stages, and compared to p27Kip1, the related family members, exhibit different activities. Previously studies on p27, cyclin kinase inhibitors, have been shown that p27 related to cell proliferation and differentiation. However, The experiment result from the study group of Stuart J. Shankland suggested that p27 played a double sward role in cell programmed death. p27-/- cells could lead to decrease CDK2 activity. 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. RobertsCDK inhibitors: positive and negative regulators of G1-phase progressionGenes Dev. 1999 13: 1501-1512 Related posts Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27
Please Rate this Article 5 out of 54 out of 53 out of 52 out of 51 out of 5
Not yet Rated
