Table of Contents

Volume 1, Issue 1

  January 2002

  Pages 1 - 93

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 Issue Catalogue (MARC XML)

EDITORIAL

Open Access Article

Introducing Cell Cycle

Arthur B. Pardee
Page 1
http://dx.doi.org/10.4161/cc.1.1.91
Abstract | PDF

No Abstract Available

Open Access Article

Basic Cell Cycle and Cancer Research: Is Harmony Possible?

Mikhail V. Blagosklonny
Page 2
http://dx.doi.org/10.4161/cc.1.1.92
Abstract | PDF

No Abstract Available

Open Access Article

Nobel Prize: Heroes for a Heroic Age

Robert T. Johnson and C. Stephen Downes
Pages 3 - 4
http://dx.doi.org/10.4161/cc.1.1.93
Abstract | PDF

Nobel Prize in Medicine (2001) awarded to Leland H. Hartwell, R. Timothy Hunt, Sir Paul M. Nurse




PORTRAIT OF AN EDITORIAL BOARD MEMBER

Open Access Article

Nobel Prize: Heroes for a Heroic Age

Chris Norbury
Pages 5 - 6
http://dx.doi.org/10.4161/cc.1.1.94
Abstract | PDF

Portrait of Sir Paul Nurse




MINI-REVIEW

Open Access Article

Anthrax, MEK and Cancer

J.F. Bodart, A. Chopra, X. Liang and N. Duesbery
Pages 7 - 12
http://dx.doi.org/10.4161/cc.1.1.95
Abstract | PDF

The MEK family of protein kinases plays key roles in regulating cellular responses to mitogens as well as environmental stress. Inappropriate activation of these kinases contributes to tumorigenesis. In contrast, anthrax lethal factor, the principal virulence factor of anthrax toxin, has been demonstrated to selectively inactivate MEKs. In this article we will discuss recent advances in our understanding of molecular aspects of the pathogenesis of anthrax, emphasizing the potential role of MEK signalling in this disease, and outline novel strategies to use anthrax lethal toxin in the treatment of cancer.

Key Words

Anthrax, MEK, MAPK, Cancer




REVIEW

Open Access Article

DNA-Damage-Independent Checkpoints: Yeast and Higher Eukaryotes

Adrian P.L Smith, Juan F. Gimenez-Abian and Duncan J. Clarke
Pages 13 - 29
http://dx.doi.org/10.4161/cc.1.1.96
Abstract | PDF

No Abstract Available

Key Words

Cell Cycle, Mitotic Checkpoints, Topoisomerase II, Anaphase, Mitotic Exit, Spindle Assembly




VIEWS AND COMMENTARIES

Open Access Article

Checkpoints that Count

Robert L. Margolis
Pages 30 - 31
http://dx.doi.org/10.4161/cc.1.1.97
Abstract | PDF

No Abstract Available

Key Words

Checkpoints, Cdk, Cdc3, Drosophila, Septin Ring

Open Access Article

D1 in G2

Charles J. Sherr
Pages 32 - 34
http://dx.doi.org/10.4161/cc.1.1.106
Abstract | PDF

No Abstract Available

Key Words

D-type Cyclins, Cyclin D1, Ras

Open Access Article

Not Just a CDK Inhibitor: Regulation of Transcription by p21^{WAF1/CIP1/SDI1}

Neil D. Perkins
Pages 35 - 37
http://dx.doi.org/10.4161/cc.1.1.98
Abstract | PDF

No Abstract Available

Key Words

D-type Cyclins, Cyclin D1, Ras




EXPERIMENTAL PAPERS

Open Access Article

Phosphorylation of the Septin Cdc3 in G1 by the Cdc28 Kinase Is Essential for Efficient Septin Ring Disassembly


Pages 38 - 45
http://dx.doi.org/10.4161/cc.1.1.99
Abstract | PDF

The septins constitute a family of filament-forming proteins ubiquitous in eukaryotic species. We demonstrate here that the Saccharomyces cerevisiae septin, Cdc3, is a substrate of the cell cycle regulatory cyclin-dependent kinase (Cdk), Cdc28. Two serines near the C-terminus of Cdc3 are phosphorylated in a Cdc28-dependent manner. Analysis of a mutant allele that cannot be phosphorylated at these sites revealed an effect of Cdc28 phosphorylation of Cdc3 at the time of budding. Immunofluorescence analysis of wild-type and mutant Cdc3 indicated that prevention of phosphorylation at Cdc28-dependent sites impairs the disassembly of the old septin ring, which is inherited at mitosis but which usually disappears immediately prior to assembly of a new ring. Furthermore, immunofluorescence analysis of septin ring dynamics in a G1 cyclin (Cln) mutant suggests that G1 cyclin function is required for efficient ring disassembly. Thus, phosphorylation of Cdc3 by the Cdc28 kinase at the end of G1 may facilitate initiation of a new cell cycle by promoting disassembly of the obsolete septin ring from the previous cell cycle.

Key Words

G1, Cdc3, Septin Ring, Drosophila, Cytokinesis

Open Access Article

Ras Is Active Throughout the Cell Cycle, but Is Able to Induce Cyclin D1 Only During G2 Phase

Gaurisankar Sa, Masahiro Hitomi, Jyoti Harwalkar, Andrew W. Stacey, Guan Chen and Dennis W. Stacey
Pages 46 - 54
http://dx.doi.org/10.4161/cc.1.1.100
Abstract | PDF

The control of cell cycle progression has been studied in asynchronous cultures using image analysis and time lapse techniques. This approach allows determination of the cycle phase and signaling properties of individual cells, and avoids the need for synchronization. In past studies this approach demonstrated that continuous cell cycle progression requires the induction of cyclin D1 levels by Ras, and that this induction takes place during G2 phase. These studies were designed to understand how Ras could induce cyclin D1 levels only during G2 phase. First, in studies with a Ras-specific promoter and cellular migration we find that endogenous Ras is active in all cell cycle phases of actively cycling NIH3T3 cells. This suggests that cyclin D1 induction during G2 phase is not the result of Ras activation specifically during this cell cycle period. To confirm this suggestion oncogenic Ras, which is expected to be active in all cell cycle phases, was microinjected into asynchronous cells. The injected protein induced cyclin D1 levels rapidly, but only in G2 phase cells. We conclude that in the continuously cycling cell the targets of Ras activity are controlled by cell cycle phase, and that this phenomenon is vital to cell cycle progression.

Key Words

Cell Cycle, Ras, Cyclin D1, G2-Phase, Asynchronous Culture

Open Access Article

Identification of Promoter Elements Responsible for Transcriptional Inhibition of Polo-like Kinase 1 and Topoisomerase IIα Genes by p21^{WAF1/CIP1/ SDI1}

Hongming Zhu, Bey-Dih Chang, Takeshi Uchiumi and Igor B. Roninson
Pages 55 - 63
http://dx.doi.org/10.4161/cc.1.1.101
Abstract | PDF

Induction of p21^{WAF1/CIP1/SDI1}, a physiological mediator of cell cycle arrest, inhibits multiple genes involved in cell division. We have investigated the determinants of p21-mediated inhibition of two of these genes, polo-like kinase 1 (PLK1) and topoisomerase IIa (TOPO IIa). p21 expression from an inducible promoter in human HT1080 cells rapidly decreases cellular levels of PLK1 and TOPO IIa RNA without decreasing their RNA stability. p21 also inhibits reporter gene expression from the PLK1 and TOPO IIa promoters in transient and stable transfection assays. Promoter mutagenesis studies show that inhibition of the PLK1 promoter by p21 is mediated in part by tandem sequences CDE (cell cycle-dependent element) and CHR (cell cycle genes homology region). p21 response of the TOPO IIa promoter was found to be mediated through CDE (but not CHR) and the inverted CCAAT box 1 (ICB1). The extent of PLK1 and TOPO IIa promoter inhibition and the effects of promoter mutations differ under the conditions of growth arrest produced by p21 induction or by mimosine, a cell cycle inhibitor that increases p21 RNA but not protein expression in HT1080 cells. These results indicate that inhibition of cell division-associated genes by p21 is mediated by different but overlapping mechanisms, which are not a general consequence of cell cycle arrest.

Key Words

p21^{WAF1/CIP1/SDI1}, Polo-like Kinase, Topoisomerase II, Regulation of Transcription, CDE, CHR, ICB

Open Access Article

Inhibition of Transcription Results in Accumulation of Wt p53 Followed by Delayed Outburst of p53-Inducible Proteins: p53 as a Sensor of Transcriptional Integrity

Mikhail V. Blagosklonny, Zoya N. Demidenko and Tito Fojo
Pages 64 - 71
http://dx.doi.org/10.4161/cc.1.1.102
Abstract | PDF

Here we investigate activation of the p53 pathway by inhibition of transcription. Comparison of cells with either mutant p53 or wt p53 indicated that inhibition of p53-dependent transcription is necessary and sufficient for wt p53 accumulation. In addition to Mdm-2, p21 is required for effective p53 degradation. Transient inhibition of transcription resulted in initial downregulation of p21 and Mdm-2 leading to accumulation of wt p53. This was followed by induction of p21 and Mdm-2, normalization of p53 levels, and p21-dependent growth arrest. Although simultaneous induction of p53 and p21 could be detected by immunoblot, levels of p53 and p21 were discordant in individual cells. By inducing p21 and Mdm-2, p53 discriminates between transient and sustained inhibition of transcription. Transient inhibition results in p21-dependent growth, while sustained inhibition of transcription leads to p53-facilitated cell death. One can envision p53 as a physiological sensor of transcriptional integrity. Transient inhibition of p53- stimulated transcription by numerous stimuli including nucleotide depletion, hypoxia, UV light may be an prevalent mechanism of activation of wt p53 and its downstream pathways.

Key Words

Apoptosis, Growth Arrest, Mdm-2, p21, p53

Open Access Article

A Mammalian In Vitro Centriole Duplication System: Evidence for Involvement of CDK2/Cyclin E and Nucleophosmin/B23 in Centrosome Duplication

Pheruza Tarapore, Masaru Okuda and Kenji Fukasawa
Pages 72 - 78
http://dx.doi.org/10.4161/cc.1.1.103
Abstract | PDF

Centrosome duplication in mammalian cells is a highly regulated process, occurs in coordination of other cell cycle events. However, molecular exploration of this important cellular process had been difficult due to unavailability of a simple assay system. Here, using centrosomes loosely associated with nuclei isolated from cultured cells, we developed a cell-free centriole (duplication unit of the centrosome) duplication system: unduplicated centrosomes bound to the nuclei are able to undergo duplication in the presence of G1/S extracts. We show that the ability of G1/S extracts to induce centriole duplication in vitro depends on the presence of active CDK2/cyclin E. It has been shown that dissociation of centrosomal nucleophosmin (NPM)/B23 triggered by CDK2/cyclin E-mediated phosphorylation is required for initiation of centrosome duplication. We show that centriole duplication is blocked when nuclei were preincubated with the anti-NPM/B23 antibody that prevents phosphorylation of NPM/B23 by CDK2/cyclin E. These studies provide not only direct evidence for the requirement of CDK2/cyclin E and phosphorylation of NPM/B23 for centrosomes to initiate duplication, but a valuable experimental system for further exploration of the molecular regulation of centrosome duplication in somatic cells of higher animals.

Open Access Article

Enhanced Sensitivity of G1 Arrested Human Cancer Cells Suggests a Novel Therapeutic Strategy Using a Combination of Simvastatin and TRAIL

Zhaoyu Jin, David T. Dicker and Wafik S. El-Deiry
Pages 79 - 86
http://dx.doi.org/10.4161/cc.1.1.104
Abstract | PDF

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells over normal cells. To study the relationship between cell cycle progression and TRAIL-induced apoptosis, SW480 colon cancer and H460 lung cancer cell lines were examined for their sensitivity to TRAIL after arrest in different cell cycle phases. Cells were synchronized in G0/G1, S, and G2/M phase by serum starvation, aphidicolin, or nocodazole treatment, respectively. We found that arrest of cells in G0/G1 phase confers significantly higher susceptibility to TRAIL-induced apoptosis as compared to cells in late G1, S, or G2/M phase. To determine if cell cycle phase could be harnessed for therapeutic gain in the presence of TRAIL, we used the HMG-CoA reductase inhibitor, Simvastatin and lovastatin, to enrich a cancer cell population in G0/G1. Both simvastatin and lovastatin significantly augmented TRAIL-induced apoptosis in tumor cells, but not in normal keratinocytes. The results indicate that TRAIL, in combination with a HMG-CoA reductase inhibitor, may have therapeutic potential in the treatment of human cancer.

Key Words

TRAIL, Synchronization, Simvastatin, Cancer Therapy, Lovastatin, Cell Cycle, Apoptosis

Open Access Article

The Cyclin-Dependent Kinase Inhibitor Butyrolactone Is a Potent Inhibitor of p21^WAF1/CIP1 Expression


Pages 87 - 93
http://dx.doi.org/10.4161/cc.1.1.105
Abstract | PDF

Butyrolactone I (BL) is a competitive inhibitor of ATP for binding and activation of cyclin-dependent kinases and is a potent inhibitor of cell cycle progression. Treatment of H460 human lung and SW480 human colon cancer cells with doses of BL that exceed the Ki for CDK inhibition but which are much lower than doses required to inhibit MAPK, PKA, PKC, or EGFR lead to a rapid significant reduction of endogenous p21 protein expression. BL-dependent inhibition of p21 expression appears to be p53-independent. BL-dependent p21 degradation was blocked by lactacystin, consistent with the hypothesis that there is accelerated p21 proteasomal degradation in the presence of BL. BL also inhibited the p53-dependent increase of p21 protein expression in cells exposed to the DNA damaging agent etoposide, and favored a greater G2/M arrest as compared to the non-BL exposed cells. BL accelerated the degradation of exogenously expressed p21 that was not observed with a C-terminal truncated form of p21. Degradation of exogenous p21 led to a shift to G2 accumulation in the cells exposed to BL. We conclude that BL has effects on the cell cycle beyond its role as a CDK inhibitor and can be used as a novel tool to study the mechanism of p21 degradation and the consequences towards p21-dependent checkpoints.

Key Words

p21, Butyrolactone, Proteasome, Cell Cycle, Checkpoint