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CDK inhibitors: positive and negative regulators of G1-phase progression.
This work challenges previous assumptions about how the G1/S transition of the mammalian cell cycle is governed, helps explain some enigmatic features of cell cycle control that also involve the functions of the retinoblastoma protein (Rb) and the INK4 proteins, and changes the thinking about how either p16 loss or overexpression of cyclin D-dependent kinases contribute to cancer.
Cancer Cell Cycles
- C. Sherr
- Biology, MedicineScience
- 6 December 1996
Genetic alterations affecting p16INK4a and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development.
Inhibitors of mammalian G1 cyclin-dependent kinases.
The discoveD] of mammalian G1 cyclins just 4 years ago and the identification of their associated cyclin-dependent kinases provided key insights soon thereafter as to how progression through the first gap phase of the mammalian cell cycle might be regulated positively.
Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
It is demonstrated that glycogen synthase kinase-3beta (GSK-3 beta) phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclinD1 turnover, which leads to proteasomal degradation of D1 and linked to phosphorylation and proteolytic turnover of cyclin L1 and its subcellular localization during the cell division cycle.
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF
The RB and p53 pathways in cancer.
Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization.
MEFs that survive myc overexpression sustain p53 mutation or ARF loss during the process of establishment and become immortal, and ARF regulates a p53-dependent checkpoint that safeguards cells against hyperproliferative, oncogenic signals.
The Pezcoller lecture: cancer cell cycles revisited.
- C. Sherr
- Biology, MedicineCancer research
- 15 July 2000
Lesions in the p16--cyclin D-CDK4--Rb and ARF--Mdm2--p53 pathways occur so frequently in cancer, regardless of patient age or tumor type, that they appear to be part of the life history of most, if not all, cancer cells.
The p21Cip1 and p27Kip1 CDK ‘inhibitors’ are essential activators of cyclin D‐dependent kinases in murine fibroblasts
In the absence of both CKIs, the severe reduction in cyclin D‐dependent kinase activity was well tolerated and had no overt effects on the cell cycle.
p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest.
Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.