A cell cycle-regulated inhibitor of cyclin-dependent kinases.

AbstractThe cyclin dependent kinases (CDKs), formed by complexes between Cdc2p and the B-cyclins Cig2p and Cdc13p, have a central role in regulating the fission yeast cell cycle and maintaining genomic stability. The CDK Cig2p/Cdc2p controls the onset of S-phase and the CDK Cdc13p/Cdc2p controls the onset of mitosis and ensures that there is only one S-phase in each cell. Cdc13p/Cdc2p can replace Cig2p/Cdc2p for the onset of S-phase, suggesting that the increasing activity of a single CDK during the cell cycle is sufficient to drive a cell in an orderly fashion into S-phase and into mitosis. If S-phase is incomplete, then inhibition of Cdc13p/Cdc2p prevents cells with unreplicated DNA from undergoing a catastrophic entry into mitosis. Control of CDK activity is also important to allow cells to exit the cell cycle and accumulate in G1 in response to nutritional deprivation and the presence of pheromone.

Download Full-text

p27Kip1 induces an accumulation of the repressor complexes of E2F and inhibits expression of the E2F-regulated genes.

Molecular Biology of the Cell ◽

10.1091/mbc.8.9.1815 ◽

1997 ◽

Vol 8 (9) ◽

pp. 1815-1827 ◽

Cited By ~ 14

Author(s):

P Shiyanov ◽

S Hayes ◽

N Chen ◽

D G Pestov ◽

L F Lau ◽

...

Keyword(s):

Cell Cycle ◽

Binding Sites ◽

Culture Medium ◽

Cyclin E ◽

Cyclin A ◽

Cyclin Dependent Kinase ◽

Binding Motifs ◽

Cyclin Dependent Kinases ◽

Cell Cycle Inhibition ◽

A Cell

p27Kip1 is an inhibitor of the cyclin-dependent kinases and it plays an inhibitory role in the progression of cell cycle through G1 phase. To investigate the mechanism of cell cycle inhibition by p27Kip1, we constructed a cell line that inducibly expresses p27Kip1 upon addition of isopropyl-1-thio-beta-D-galactopyranoside in the culture medium. Isopropyl-1-thio-beta-D-galactopyranoside-induced expression of p27Kip1 in these cells causes a specific reduction in the expression of the E2F-regulated genes such as cyclin E, cyclin A, and dihydrofolate reductase. The reduction in the expression of these genes correlates with the p27Kip1-induced accumulation of the repressor complexes of the E2F family of factors (E2Fs). Our previous studies indicated that p21WAF1 could disrupt the interaction between cyclin/cyclin-dependent kinase 2 (cdk2) and the E2F repressor complexes E2F-p130 and E2F-p107. We show that p27Kip1, like p21WAF1, disrupts cyclin/cdk2-containing complexes of E2F-p130 leading to the accumulation of the E2F-p130 complexes, which is found in growth-arrested cells. In transient transfection assays, expression of p27Kip1 specifically inhibits transcription of a promoter containing E2F-binding sites. Mutants of p27Kip1 harboring changes in the cyclin- and cdk2-binding motifs are deficient in inhibiting transcription from the E2F sites containing reporter gene. Moreover, these mutants of p27Kip1 are also impaired in disrupting the interaction between cyclin/cdk2 and the repressor complexes of E2Fs. Taken together, these observations suggest that p27Kip1 reduces expression of the E2F-regulated genes by generating repressor complexes of E2Fs. Furthermore, the results also demonstrate that p27Kip1 inhibits expression of cyclin A and cyclin E, which are critical for progression through the G1-S phases.

Download Full-text

Cyclin-dependent Kinases Phosphorylate p73 at Threonine 86 in a Cell Cycle-dependent Manner and Negatively Regulate p73

Journal of Biological Chemistry ◽

10.1074/jbc.m300251200 ◽

2003 ◽

Vol 278 (30) ◽

pp. 27421-27431 ◽

Cited By ~ 38

Author(s):

Christian Gaiddon ◽

Maria Lokshin ◽

Isabelle Gross ◽

Danielle Levasseur ◽

Yoichi Taya ◽

...

Keyword(s):

Cell Cycle ◽

Dependent Manner ◽

Cyclin Dependent Kinases ◽

A Cell ◽

Cycle Dependent

Download Full-text

The oscillation of mitotic kinase governs cell cycle latches

10.1101/2021.12.07.471646 ◽

2021 ◽

Author(s):

Bela Novak ◽

John J Tyson

Keyword(s):

Cell Cycle ◽

Negative Feedback ◽

Molecular Switches ◽

Feedback Loops ◽

Yeast Cells ◽

Cyclin Dependent Kinases ◽

Mitotic Kinase ◽

Daughter Cells ◽

Negative Feedback Loops ◽

A Cell

SummaryIn order to transmit a eukaryotic cell’s genome accurately from mother cell to daughter cells, it is essential that the basic events of the cell division cycle (DNA synthesis and mitosis) occur once and only once per cycle, i.e., that a cell progresses irreversibly from G1 to S to G2 to M and back to G1. Irreversible progression through the cell cycle is assured by a sequence of ‘latching’ molecular switches, based on molecular interactions among cyclin-dependent kinases and their auxiliary partners. Positive feedback loops (++ or −−) create bistable switches with latching properties, and negative feedback loops drive progression from one stage to the next. In budding yeast (Saccharomyces cerevisiae) these events are coordinated by double-negative feedback loops between Clb-dependent kinases (Clb1-6) and their antagonists (APC:Cdh1 and Sic1). If the coordinating signal is compromised, either by deletion of Clb1-5 proteins or expression of non-degradable Clb2, then irreversibility is lost and yeast cells exhibit multiple rounds of DNA replication or mitotic exit events (Cdc14 endocycles). Using mathematical modelling of a stripped-down control network, we show how endocycles arise because the switches fail to latch, and the gates swing back and forth by the action of the negative feedback loops.

Download Full-text

CP60: a microtubule-associated protein that is localized to the centrosome in a cell cycle-specific manner.

Molecular Biology of the Cell ◽

10.1091/mbc.6.12.1673 ◽

1995 ◽

Vol 6 (12) ◽

pp. 1673-1684 ◽

Cited By ~ 29

Author(s):

D R Kellogg ◽

K Oegema ◽

J Raff ◽

K Schneider ◽

B M Alberts

Keyword(s):

Cell Cycle ◽

Dependent Manner ◽

Multiprotein Complex ◽

Cyclin Dependent Kinases ◽

A Cell ◽

Late Telophase ◽

Cycle Dependent ◽

Centrosomal Proteins ◽

Drosophila Embryos

DMAP190 is a microtubule-associated protein from Drosophila that is localized to the centrosome. In a previous study, we used affinity chromatography to identify proteins that interact with DMAP190, and identified a 60-kDa protein that we named DMAP60 (Kellogg and Alberts, 1992). Like DMAP190, DMAP60 interacts with microtubules and is localized to the centrosome, and the two proteins associate as part of a multiprotein complex. We now report the cloning and sequencing of the cDNA encoding DMAP60. The amino acid sequence of DMAP60 is not homologous to any protein in the database, although it contains six consensus sites for phosphorylation by cyclin-dependent kinases. As judged by in situ hybridization, the gene for DMAP60 maps to chromosomal region 46A. In agreement with others working on Drosophila centrosomal proteins, we have changed the names for DMAP190 and DMAP60 to CP190 and CP60, respectively, to give these proteins a consistent nomenclature. Antibodies that recognize CP60 reveal that it is localized to the centrosome in a cell cycle-dependent manner. The amount of CP60 at the centrosome is maximal during anaphase and telophase, and then drops dramatically during late telophase or early interphase. This dramatic disappearance of CP60 may be due to specific proteolysis, because CP60 contains a sequence of amino acids similar to the "destruction box" that targets cyclins for proteolysis at the end of mitosis. Starting with nuclear cycle 12, CP60 and CP190 are both found in the nucleus during interphase. CP60 isolated from Drosophila embryos is highly phosphorylated, and dephosphorylated CP60 is a good substrate for cyclin B/p34cdc2 kinase complexes. A second kinase activity capable of phosphorylating CP60 is present in the CP60/CP190 multiprotein complex. We find that bacterially expressed CP60 binds to purified microtubules, and this binding is blocked by CP60 phosphorylation.

Download Full-text

Seliciclib, a cell-cycle modulator that acts through the inhibition of cyclin-dependent kinases

Expert Opinion on Drug Discovery ◽

10.1517/17460441.3.1.131 ◽

2007 ◽

Vol 3 (1) ◽

pp. 131-143 ◽

Cited By ~ 7

Author(s):

Robert C Jackson ◽

Anna L Barnett ◽

Steven J McClue ◽

Simon R Green

Keyword(s):

Cell Cycle ◽

Cyclin Dependent Kinases ◽

A Cell

Download Full-text

The Less Known Cyclins—Uncovered

Applied Sciences ◽

10.3390/app11052320 ◽

2021 ◽

Vol 11 (5) ◽

pp. 2320

Author(s):

Agnieszka Żuryń ◽

Aleksandra Opacka ◽

Adrian Krajewski ◽

Wioletta Zielińska ◽

Alina Grzanka

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Differentiation ◽

Cancer Cells ◽

Present Report ◽

Life Stage ◽

Cyclin Dependent Kinases ◽

Current State ◽

Different Types ◽

A Cell

Cyclins belong to a group of proteins that are cyclically produced and destructed in a cell. Cyclins are a family of proteins that are a key component of the cell cycle regulating system, which level of expression depends on the phase of the cycle. Cyclins regulate the activity of cyclin-dependent kinases (Cdk), thanks to which they influence the length of individual phases of the cell cycle and also determine whether the cell can enter the next life stage. Proper expression of cyclins plays an important role in processes such as proliferation, transcription, DNA repair and cell differentiation. However, dysregulation of their expression is one of the most important disorders leading to the development of different types of cancer, which suggests that cyclins can be defined as a prognostic marker. Currently, we may distinguish >10 members of the cyclins family participating in the division of human cells. The group of less known cyclins includes C, F, G, H, I, J, K, L, M, O, T and Y cyclins. The present report demonstrates the current state of knowledge considering less known cyclins and their role in normal and cancer cells.

Download Full-text