The p21Cip1 and p27Kip1 CDK `inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts

Cheng, Mangeng

doi:10.1093/emboj/18.6.1571

Cited by 1,047 publications

(975 citation statements)

References 80 publications

Supporting

Mentioning

887

Contrasting

Unclassified

Order By: Relevance

“…At substoichiometric levels, p21 Waf1 is essential for cellular proliferation. It promotes the association of cdk4 with D-type cyclins (Cheng et al, 1999) and provides a localization signal for their nuclear import (Deng et al, 1995). Upon growth factor deprivation or in response to genotoxic stress, D cyclins are rapidly destroyed (Diehl et al, 1998); their degradation causes the release of p21 Waf1 molecules from cdk4/6 complexes to arrest progression in G 1 , at least in part, by inhibiting cdk2 activity (Agami and Bernards, 2002).…”

Section: Discussionmentioning

confidence: 99%

Regulation of normal cell cycle progression by flavin-containing oxidases

Prakash¹,

Toledo²,

Pandey³

et al. 2007

Oncogene

View full text Add to dashboard Cite

Mechanisms underlying the role of reactive oxygen species (ROS) generated by flavin-containing oxidases in regulating cell cycle progression were examined in human and rodent fibroblasts. Incubation of confluent cell cultures with nontoxic/nonclastogenic concentrations of the flavoprotein inhibitor, diphenyleneiodonium (DPI), reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity and basal ROS levels, but increased proteolysis of cyclin D1, p21 Waf1 and phospho-p38 MAPK . When these cells were allowed to proliferate by subculture in DPI-free medium, an extensive G 1 delay was observed with concomitant activation of p53/p21 Waf1 signaling and reduced phosphorylation of mitogen-activated kinases. Compensation for decreased oxidant generation by simultaneous exposure to DPI and nontoxic doses of the ROS generators, c-radiation or t-butyl-hydroperoxide, attenuated the G 1 delay. Whereas the DPI-induced G 1 checkpoint was completely dependent on PHOX91, ATM and WAF1, it was only partially dependent on P53. Interestingly, G 1 to S progression was not affected when another flavin-containing enzyme, nitric oxide synthase, was inhibited nor was it associated with changes in mitochondrial membrane potential. Proliferating cells treated with DPI also experienced a significant but attenuated delay in G 2 . We propose that ATM performs a critical function in mediating normal cellular proliferation that is regulated by nonphagocytic NAD(P)H oxidase enzymes activity, which may serve as a novel target for arresting cancer cells in G 1 .

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of normal cell cycle progression by flavin-containing oxidases

Prakash¹,

Toledo²,

Pandey³

et al. 2007

Oncogene

View full text Add to dashboard Cite

show abstract

“…The residual p21 associated with cyclin D1 may in fact promote the activity of this cdk complex as p21 acts as an assembly factor when present at a lower concentration (LaBaer et al, 1997). This notion has recently been con®rmed by the ®nding that mouse ®broblast defective in both p21 and p27 fail to assemble cyclin D-cdk4 complexes (Cheng et al, 1999). The positive action of p21 on D-type cyclincdk complexes provides an explanation as to why these proteins may share a common proteolytic machinery.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of p21 in MCF-7 cells is overcome by its coordinated stabilization with D-type cyclins

1999

View full text Add to dashboard Cite

Coordinated accumulation of cyclin D1 and D3 is observed in 15% of primary breast cancers and in the breast cancer cell line MCF-7 this simultaneous overexpression is due to a defect in their ubiquitin-mediated proteolysis. The F-box protein Skp2 is a component of an SCF ubiquitin ligase complex and can associate with cyclin D1 and the cdk inhibitor p21 (Zhong-Kang et al., 1998). We extend this observation and show that cyclin D3 can also associate with Skp2 suggesting that cyclins D1, D3 and p21 may share the same SCF complex. In agreement with this hypothesis we report here that in primary breast cancers and in MCF-7 cells where cyclins D1 and D3 are elevated the level of p21 is also elevated. Further, we demonstrate that the turnover of p21 protein is reduced in MCF-7 cells. We show that p21 is active as a cdk inhibitor in this cell line but that the presence of elevated levels of cyclin D3 titrates p21 away from cyclin D1-cdk4/6 complexes and cdk2 complexes resulting in increased kinase activities. Our results suggest that a defect in the SCF complex may occur in 15 ± 20% of breast cancers and that the resulting coordinated elevation of cyclins D1 and D3 overcomes the inhibition of cell cycle progression by p21. We propose that in the context of cyclins D1 and D3 overexpression, p21 may promote cell cycle progression.

show abstract

“…RB phosphorylation therefore shifts from a mitogendependent (cyclin D) to a mitogen-independent (cyclin E) mechanism, underlying the commitment to cell cycle progression at the R point [8]. According to this model, the accumulation of especially labile cyclins D over an inhibitory threshold imposed by INK4 CDK inhibitors best fulfills Pardee's criteria for the R-point protein [3,4,12]. The role of CDK "inhibitors" of the cip/kip family including p27 kip1 in this model is complex and not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Nature of the Critical Labile Event That Controls RB Phosphorylation in the Cyclic AMP-Dependent Cell Cycle of Thyrocytes in Primary Culture

Roger

Demartin

Dumont

1999

Experimental Cell Research

View full text Add to dashboard Cite

This study addresses the nature of the critical labile event that couples at restriction point mitogenic cascades with the autonomous part of the cell cycle. In primary cultures of dog thyroid epithelial cells, kinetic experiments indicate that a labile cAMP-dependent event positively controls a late G1 commitment to DNA replication and RB phosphorylation. As previously shown in this system, the cAMP-dependent mitogenic pathway differs from the most generally envisaged growth factor cascades as it stimulates the accumulation of p27 kip1 but not of cyclins D. Nevertheless, cyclin D3 and CDK4 activity are essential in the cAMP-dependent mitogenesis, and cAMP unmasks the DCS-22 epitope of cyclin D3 and induces the nuclear translocations and assembly of cyclin D3 and CDK4 in a complex that also contains p27 kip1 . Unexpectedly, the washing out of forskolin rapidly arrested S phase entry and the accumulation of hyperphosphorylated RB, but did not reverse any of the above events associated with cyclin D3-CDK4 activation. This implies that even after induction of stable nuclear cyclin D3-CDK4 complexes, dog thyrocytes still depend on cAMP for RB phosphorylation and commitment to DNA synthesis, which suggests that a key labile event responsible for a last control of restriction point passage remains to be uncovered, in the cAMP-dependent cell cycle of dog thyrocytes and possibly other systems.

show abstract

The p21Cip1 and p27Kip1 CDK `inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts

Cited by 1,047 publications

References 80 publications

Regulation of normal cell cycle progression by flavin-containing oxidases

Regulation of normal cell cycle progression by flavin-containing oxidases

Inhibitory effect of p21 in MCF-7 cells is overcome by its coordinated stabilization with D-type cyclins

Nature of the Critical Labile Event That Controls RB Phosphorylation in the Cyclic AMP-Dependent Cell Cycle of Thyrocytes in Primary Culture

Contact Info

Product

Resources

About