The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts.
Mangeng Cheng,Paul Olivier,Paul Olivier,J. Alan Diehl,J. Alan Diehl,Matthew L. Fero,Matthew L. Fero,Martine F. Roussel,James M. Roberts,James M. Roberts,Charles J. Sherr,Charles J. Sherr +11 more
TLDR
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.Abstract:
The widely prevailing view that the cyclin-dependent kinase inhibitors (CKIs) are solely negative regulators of cyclin-dependent kinases (CDKs) is challenged here by observations that normal up-regulation of cyclin D- CDK4 in mitogen-stimulated fibroblasts depends redundantly upon p21(Cip1) and p27(Kip1). Primary mouse embryonic fibroblasts that lack genes encoding both p21 and p27 fail to assemble detectable amounts of cyclin D-CDK complexes, express cyclin D proteins at much reduced levels, and are unable to efficiently direct cyclin D proteins to the cell nucleus. Restoration of CKI function reverses all three defects and thereby restores cyclin D activity to normal physiological levels. 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.read more
Citations
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CDK inhibitors: positive and negative regulators of G1-phase progression
TL;DR: 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.
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Inhibition of Histone Deacetylase Activity by Butyrate
TL;DR: The model is proposed in which inhibition of Sp1/Sp3-associated HDAC activity leads to histone hyperacetylation and transcriptional activation of the p21(Waf1/Cip1) gene, which inhibits cyclin-dependent kinase 2 activity and thereby arrests cell cycling.
References
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Journal ArticleDOI
WAF1, a potential mediator of p53 tumor suppression
Wafik S. El-Deiry,Takashi Tokino,Victor E. Velculescu,Daniel B. Levy,Ramon Parsons,Jeffrey M. Trent,D Lin,W. Edward Mercer,Kenneth W. Kinzler,Bert Vogelstein +9 more
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
Journal ArticleDOI
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases
TL;DR: In this article, an improved two-hybrid system was employed to isolate human genes encoding Cdk-interacting proteins (Cips) and found that CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2.
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Cancer Cell Cycles
TL;DR: 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.
Journal ArticleDOI
High-efficiency transformation of mammalian cells by plasmid DNA.
TL;DR: A simple calcium phosphate transfection protocol and neo marker vectors that achieve highly efficient transformation of mammalian cells are described and linear DNA is almost inactive in mammalian cells.
Journal ArticleDOI
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.
TL;DR: It is shown that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3, and it is demonstrated that PKB is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC).