scholarly journals Mad1 Function in Cell Proliferation and Transcriptional Repression Is Antagonized by Cyclin E/CDK2

2005 ◽  
Vol 280 (16) ◽  
pp. 15489-15492 ◽  
Author(s):  
Sabine Rottmann ◽  
Annette R. Menkel ◽  
Caroline Bouchard ◽  
Jürgen Mertsching ◽  
Peter Loidl ◽  
...  
Keyword(s):  
Phase Transition ◽  
Cell Proliferation ◽  
Transcriptional Repression ◽  
Cyclin E ◽  
S Phase ◽  
Cellular Behavior ◽  
Corepressor Complex ◽  
Repressor Complex ◽  
Phase Progression ◽  
Cell Cycle Regulator Cyclin

The transcription factors of the Myc/Max/Mad network play essential roles in the regulation of cellular behavior. Mad1 inhibits cell proliferation by recruiting an mSin3-corepressor complex that contains histone deacetylase activity. Here we demonstrate that Mad1 is a potent inhibitor of the G1to S phase transition, a function that requires Mad1 to heterodimerize with Max and to bind to the corepressor complex. Cyclin E/CDK2, but not cyclin D and cyclin A complexes, fully restored S phase progression. In addition inhibition of colony formation and gene repression by Mad1 were also efficiently antagonized by cyclin E/CDK2. This was the result of cyclin E/CDK2 interfering with the interaction of Mad1 with HDAC1 and reducing HDAC activity. Our findings define a novel interplay between the cell cycle regulator cyclin E/CDK2 and Mad1 and its associated repressor complex and suggests an additional mechanism how cyclin E/CDK2 affects the G1to S phase transition.

Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation

Cell ◽  
1994 ◽  
Vol 77 (1) ◽  
pp. 107-120 ◽  
Author(s):  
Jürgen A. Knoblich ◽  
Karsten Sauer ◽  
Lynn Jones ◽  
Helena Richardson ◽  
Robert Saint ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cyclin E ◽  
S Phase ◽  
Down Regulation ◽  
Drosophila Embryogenesis ◽  
Phase Progression

PRDM14 inhibits 293T cell proliferation by influencing the G1/S phase transition

Gene ◽  
2016 ◽  
Vol 595 (2) ◽  
pp. 180-186 ◽  
Author(s):  
Yanan Lu ◽  
Zhiyi Wan ◽  
Xueqing Zhang ◽  
Xiaorong Zhong ◽  
Lei Rui ◽  
...  
Keyword(s):  
Phase Transition ◽  
Cell Proliferation ◽  
293T Cell ◽  
S Phase

scholarly journals Ectopic Expression of Cdc25A Accelerates the G1/S Transition and Leads to Premature Activation of Cyclin E- and Cyclin A-Dependent Kinases

1999 ◽  
Vol 19 (9) ◽  
pp. 6183-6194 ◽  
Author(s):  
Ida Blomberg ◽  
Ingrid Hoffmann
Keyword(s):  
Phase Transition ◽  
Cyclin E ◽  
Ectopic Expression ◽  
Cyclin A ◽  
S Phase ◽  
Important Regulator ◽  
Cycle Regulation ◽  
Cdc25a Phosphatase ◽  
Rate Limiting

ABSTRACT Human Cdc25 phosphatases play important roles in cell cycle regulation by removing inhibitory phosphates from tyrosine and threonine residues of cyclin-dependent kinases. Three human Cdc25 isoforms, A, B, and C, have been discovered. Cdc25B and Cdc25C play crucial roles at the G2/M transition. In the present study, we have investigated the function of human Cdc25A phosphatase. Cell lines that express human Cdc25A in an inducible manner have been generated. Ectopic expression of Cdc25A accelerates the G1/S-phase transition, indicating that Cdc25A controls an event(s) that is rate limiting for entry into S phase. Furthermore, we carried out a detailed analysis of the expression and activation of human Cdc25A. Activation of endogenous Cdc25A occurs during late G1 phase and increases in S and G2 phases. We further demonstrate that Cdc25A is activated at the same time as cyclin E- and cyclin A-dependent kinases. In vitro, Cdc25A dephosphorylates and activates the cyclin-Cdk complexes that are active during G1. Overexpression of Cdc25A in the inducible system, however, leads to a premature activation of both cyclin E-Cdk2 and cyclin A-Cdk2 complexes, while no effect of cyclin D-dependent kinases is observed. Furthermore, Cdc25A overexpression induces a tyrosine dephosphorylation of Cdk2. These results suggest that Cdc25A is an important regulator of the G1/S-phase transition and that cyclin E- and cyclin A-dependent kinases act as direct targets.

scholarly journals HiNF-P Directly Links the Cyclin E/CDK2/p220NPAT Pathway to Histone H4 Gene Regulation at the G1/S Phase Cell Cycle Transition

2005 ◽  
Vol 25 (14) ◽  
pp. 6140-6153 ◽  
Author(s):  
Angela Miele ◽  
Corey D. Braastad ◽  
William F. Holmes ◽  
Partha Mitra ◽  
Ricardo Medina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phase Transition ◽  
Cell Cycle ◽  
Cyclin E ◽  
S Phase ◽  
Phase Cell ◽  
Genome Replication ◽  
Dependent Manner ◽  
Histone H4 ◽  
Histone H4 Gene

ABSTRACT Genome replication in eukaryotic cells necessitates the stringent coupling of histone biosynthesis with the onset of DNA replication at the G1/S phase transition. A fundamental question is the mechanism that links the restriction (R) point late in G1 with histone gene expression at the onset of S phase. Here we demonstrate that HiNF-P, a transcriptional regulator of replication-dependent histone H4 genes, interacts directly with p220NPAT, a substrate of cyclin E/CDK2, to coactivate histone genes during S phase. HiNF-P and p220 are targeted to, and colocalize at, subnuclear foci (Cajal bodies) in a cell cycle-dependent manner. Genetic or biochemical disruption of the HiNF-P/p220 interaction compromises histone H4 gene activation at the G1/S phase transition and impedes cell cycle progression. Our results show that HiNF-P and p220 form a critical regulatory module that directly links histone H4 gene expression at the G1/S phase transition to the cyclin E/CDK2 signaling pathway at the R point.

scholarly journals A novel inhibitor of cyclin-Cdk activity detected in transforming growth factor beta-arrested epithelial cells.

1994 ◽  
Vol 14 (6) ◽  
pp. 3683-3694 ◽  
Author(s):  
J M Slingerland ◽  
L Hengst ◽  
C H Pan ◽  
D Alexander ◽  
M R Stampfer ◽  
...  
Keyword(s):  
Phase Transition ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Cyclin E ◽  
Cyclin A ◽  
S Phase ◽  
Tgf Beta ◽  
Growth Factor Beta

Transforming growth factor beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Cyclins E and A in association with Cdk2 have been shown to play a role in the G1-to-S phase transition in mammalian cells. We have studied the effects of TGF-beta-mediated growth arrest on G1/S cyclins E and A. Inhibition of cyclin A-associated kinase by TGF-beta is primarily due to a decrease in cyclin A mRNA and protein. By contrast, while TGF-beta inhibits accumulation of cyclin E mRNA, the reduction in cyclin E protein is minimal. Instead, we find that the activation of cyclin E-associated kinase that normally accompanies the G1-to-S phase transition is inhibited. A novel inhibitor of cyclin-Cdk complexes was detected in TGF-beta-treated cell lysates. Inhibition is mediated by a heat-stable protein that targets both Cdk2 and Cdc2 kinases. In G0-arrested cells, a similar inhibitor of Cdk2 kinase was detected. These data suggest the existence of an inhibitor of cyclin-dependent kinases induced under different conditions to mediate antiproliferative responses.

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