Cyclin-dependent kinases and cell-cycle transitions: does one fit all?

Hochegger, Helfrid; Takeda, Shunichi; Hunt, Tim

doi:10.1038/nrm2510

Cited by 489 publications

(430 citation statements)

References 69 publications

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“…[43][44][45] To confirm pRb under-phosphorylation as a result of TGF-␤ stimulation, we examined the amount of phosphorylation on specific residues known to be involved in cell cycle regulation. The Ser807/ 811 site is phosphorylated by cyclin D1-CDK4 complexes, 32,46 and its phosphorylation status is examined in our study. We show that, in TGF-␤-treated VICs, phosphorylated pRb (Ser807/811) is reduced by as much as 10-fold.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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Although valve interstitial cell (VIC) growth is an essential feature of injured and diseased valves, the regulation of VIC growth is poorly understood. Transforming growth factor (TGF)-␤ promotes VIC proliferation in early-stage wound repair; thus, herein, we tested the hypothesis that TGF-␤ regulates VIC proliferation under normal nonwound conditions using low-density porcine VIC monolayers. Cell numbers were counted during a 10-day period, whereas proliferation and apoptosis were quantified by bromodeoxyuridine staining and TUNEL, respectively. The extent of retinoblastoma protein phosphorylation and expression of cyclin D1, CDK 4, and p27 were compared using Western blot analysis. Adhesion was quantified using a trypsin adhesion assay, and morphological change was demonstrated by immunofluorescence localization of ␣-smooth muscle actin and vinculin. TGF-␤-treated VICs were rhomboid; significantly decreased in number, proliferation, and retinoblastoma protein phosphorylation; and concomitantly had decreased expression of cyclin D1/CDK4 and increased expression of p27. TGF-␤-treated VICs adhered better to substratum and had more vinculin plaques and ␣-smooth muscle actin stress fibers than did controls. Thus, the regulation of VIC growth by TGF-␤ is context dependent. TGF-␤ prevents excessive heart valve growth under normal physiological conditions while it promotes cell proliferation in the early stages of repair, when increased VICs are required.

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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“…In budding yeast, these efforts revealed a so-called mitotic exit network (MEN) kinase cascade [10,11,32,33]. MEN signalling triggers the transition from the mitotic anaphase through to the G1-phase of the cell cycle by inactivating mitotic CDK1, one key hallmark of the end of mitosis [5]. More specifically, after the initial activation of the GTPase Tem1p at the spindle pole body (SPB; the equivalent of centrosomes in animals), the Cdc15p protein kinase is stimulated by GTPbound Tem1p.…”

Section: Mitotic Exit Network (Men) In S Cerevisiaementioning

confidence: 99%

“…Thus, for decades intensive research efforts have been ongoing to understand the signal transduction machineries that control mitosis and cytokinesis. Not surprisingly, these studies revealed that eukaryotic cells have developed several mechanisms to ensure faithful chromosome segregation [4,5].…”

Section: Introductionmentioning

confidence: 99%

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hergovich

Hemmings

2012

Seminars in Cell & Developmental Biology

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Over the past decade Hippo kinase signalling has been established as an essential tumour suppressor pathway controlling tissue growth in flies and mammals. All members of the Hippo core signalling cassette are conserved from yeast to humans, whereby the yeast analogues of Hippo, Mats and Lats are central components of the mitotic exit network and septation initiation network in budding and fission yeast, respectively. Here, we discuss how far core Hippo signalling components in Drosophila melanogaster and mammals have reported similar mitotic functions as already established for their highly conserved yeast counterparts.

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“…During the G 1 phase, cells pass the restriction point, which is a point of no return beyond which they are irreversibly engaged in the cell cycle and do not require the presence of GF to complete mitosis (1,2). Progression in the cell cycle is controlled by the sequential, transient activation of a family of cyclin-dependent kinases (Cdks), which allow an ordered succession of the cell-cycle phases G 1 , S, G 2 , and M (4, 5), even though there appears to be a certain overlapping of the different cyclins and Cdks (6). The Cdk proteins are active only when forming a complex with their corresponding cyclin.…”

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confidence: 99%

Temporal self-organization of the cyclin/Cdk network driving the mammalian cell cycle

Gérard

Goldbeter

2009

Proc. Natl. Acad. Sci. U.S.A.

209

387

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We propose an integrated computational model for the network of cyclin-dependent kinases (Cdks) that controls the dynamics of the mammalian cell cycle. The model contains four Cdk modules regulated by reversible phosphorylation, Cdk inhibitors, and protein synthesis or degradation. Growth factors (GFs) trigger the transition from a quiescent, stable steady state to self-sustained oscillations in the Cdk network. These oscillations correspond to the repetitive, transient activation of cyclin D/Cdk4 -6 in G 1, cyclin E/Cdk2 at the G 1/S transition, cyclin A/Cdk2 in S and at the S/G2 transition, and cyclin B/Cdk1 at the G2/M transition. The model accounts for the following major properties of the mammalian cell cycle: (i) repetitive cell cycling in the presence of suprathreshold amounts of GF; (ii) control of cell-cycle progression by the balance between antagonistic effects of the tumor suppressor retinoblastoma protein (pRB) and the transcription factor E2F; and (iii) existence of a restriction point in G 1, beyond which completion of the cell cycle becomes independent of GF. The model also accounts for endoreplication. Incorporating the DNA replication checkpoint mediated by kinases ATR and Chk1 slows down the dynamics of the cell cycle without altering its oscillatory nature and leads to better separation of the S and M phases. The model for the mammalian cell cycle shows how the regulatory structure of the Cdk network results in its temporal self-organization, leading to the repetitive, sequential activation of the four Cdk modules that brings about the orderly progression along cell-cycle phases. cellular rhythms ͉ oscillations ͉ mitotic oscillator ͉ model ͉ systems biology I n the presence of sufficient amounts of growth factor (GF), mammalian cells quit a quiescent state, denoted G 0 , and start their progression in the cell cycle (1-3). During the G 1 phase, cells pass the restriction point, which is a point of no return beyond which they are irreversibly engaged in the cell cycle and do not require the presence of GF to complete mitosis (1, 2). Progression in the cell cycle is controlled by the sequential, transient activation of a family of cyclin-dependent kinases (Cdks), which allow an ordered succession of the cell-cycle phases G 1 , S, G 2 , and M (4, 5), even though there appears to be a certain overlapping of the different cyclins and Cdks (6). The Cdk proteins are active only when forming a complex with their corresponding cyclin. The cyclin D/Cdk4-6, cyclin E/Cdk2, cyclin A/Cdk2, and cyclin B/Cdk1 complexes promote, respectively, progression in G 1 , the transition to DNA replication in S, progression in S and transition to G 2 , and finally the G 2 /M transition allowing entry into mitosis (3-7). Cdk regulation is achieved through a variety of mechanisms that include association with cyclins and protein inhibitors, phosphorylationdephosphorylation (8), and cyclin synthesis or degradation (9).A number of theoretical models for the cell cycle have been proposed. Initially, these models pertained t...

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Cyclin-dependent kinases and cell-cycle transitions: does one fit all?

Cited by 489 publications

References 69 publications

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Temporal self-organization of the cyclin/Cdk network driving the mammalian cell cycle

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