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PubMedDate not supplied

Modifications of p53 protein and accumulation of p21 and gadd45 mRNA in TGF-beta 1 growth inhibited cells.

Transforming growth factory beta (TGF-beta) is a potent growth inhibitor of epithelial cells. One of the strategies used to elucidate the anti-proliferative mode of action of TGF-beta is to find out whether the receptor-generated signals interact with components of the basic machinery of the cell cycle. In this study we examined whether p53 and two other cycle inhibitory genes that can be transactivated by p53 are affected by TGF-beta 1 in epithelial cells. We show that TGF-beta 1 signalling controls the intracellular localization as well as the phosphorylation pattern and the stability of p53 protein. TGF-beta signalling also elevates the expression of p21/waf-1 and gadd45. The observed modifications in the protein suggest that p53 is involved in mediation of TGF-beta 1 growth inhibition. However, in TGF-beta 1 growth inhibited cells, wild type p53 is not required for the accumulation of the two p53 downstream targets p21/waf-1 and gadd45.

Animals↗
PubMed2000

Cell-cycle checkpoint kinases: checking in on the cell cycle.

In response to DNA damage, cell-cycle checkpoints integrate cell-cycle control with DNA repair. The idea that checkpoint controls are an integral component of normal cell-cycle progression has arisen as a result of studies in Drosophila and mice. In addition, an appreciation that DNA damage arises as a natural consequence of cellular metabolism, including DNA replication itself, has influenced thinking regarding the nature of checkpoint pathways.

Animals↗
PubMed2000

Control of plant growth and development through manipulation of cell-cycle genes.

The plant embryo is a relatively simple structure consisting of a primordial shoot and root, whose development is frozen in the form of a seed. Most development of the mature plant takes place post-embryonically, and is the consequence of cell division and organogenesis in small regions known as meristems, which originate in the embryonic shoot and root apices. Significant recent progress has been made in understanding the mechanisms that control the plant cell cycle at a molecular level, and the first attempts have been made to control plant growth through modulation of cell-cycle genes. These results suggest that there is significant potential to control plant growth and architecture through manipulation of cell division rates. However, a full realisation of the promise of such strategies will probably require a much greater understanding of cell division control and how its upstream regulation is co-ordinated by spatial relationships between cells and by environmental signals.

Cell Cycle↗
PubMed2001

Molecular markers of tumor initiation and progression.

Of the hundreds of genes and proteins reported to be altered in human cancers, only a few are sufficiently central to warrant translation into diagnostic or therapeutic tools. Three recent developments have the potential to alter radically the discovery of molecular markers: the compendium of human genes; the advent of technologies that provide the means to identify simultaneously several known and unknown genes and proteins; and an appreciation of the critical processes involved in tumor initiation and progression.

Cell Transformation, Neoplastic↗
PubMed2001

DNA damage: Chk1 and Cdc25, more than meets the eye.

Control of mitotic entry is a component of the checkpoint response that contributes to cell survival following DNA damage. In some eukaryotic cells, mitotic entry relies heavily on regulation of the state of tyrosine phosphorylation of the cyclin-dependent kinase Cdc2. Evidence that checkpoint regulation of cell-cycle progression operates through controlling the state of Cdc2 tyrosine phosphorylation exists. Whether other targets of the checkpoint pathway could play important roles in the response to DNA damage is a subject of ongoing investigations.

Animals↗
PubMed2001

Mitotic checkpoints: from yeast to cancer.

Separation of chromosomes during mitosis is monitored by a checkpoint that leads to cell-cycle arrest if the chromosomes are not properly attached to the mitotic spindle. Molecular mechanisms controlling this checkpoint have been identified. In addition, loss of this checkpoint has been shown to result in chromosome missegregation in higher eukaryotes and may contribute to the genomic instability observed in human cancers.

Adenomatous Polyposis Coli Protein↗
PubMed2001

Coordinating cell proliferation and differentiation.

Cell proliferation and differentiation are highly coordinated processes during development. Recent studies have revealed that this coordination may result from dual functions residing in the central regulators of proliferation, allowing them to also regulate differentiation. Studies have also shown that some terminally differentiated cells can be made to divide beyond their normal capacity.

Animals↗
PubMed1997

Functions of mammalian Polycomb group and trithorax group related genes.

Genes of the Polycomb and trithorax groups (PcG and trxG) are part of a cellular memory system that maintains inactive and active states of homeotic gene expression in Drosophila. Recent genetic evidence indicates that several related loci in mammals are also involved in the regulation of Hox genes. Like their Drosophila counterparts, the vertebrate gene products are components of multiprotein complexes that regulate transcriptional activation, repression and aspects of chromatin structure. Initial indications suggest the existence of a large mammalian PcG and trxG family, with a potential to encode multiple specialised functions in cell fate and cell-cycle control.

Animals↗
PubMed2000

Complexity in the spindle checkpoint.

Cell viability requires accurate chromosome segregation at mitosis. The spindle checkpoint ensures that anaphase is not attempted until the sister chromatids of each chromosome are attached to spindle microtubules from opposite poles. The checkpoint mechanism involves a signal transduction cascade that is more complex than was originally envisioned.

Animals↗
PubMed2000

The genetic control of organ growth: insights from Drosophila.

The genetic control of growth ensures that animals grow to reproducible sizes and that tumourous growth is rare. This year, the regulation of organ growth has been studied extensively in Drosophila imaginal discs, and a signalling pathway that regulates organ growth and size has been identified. Furthermore, the role of Drosophila homologues to human tumour suppressor genes and oncogenes in imaginal disc growth has been investigated.

Animals↗
PubMed2000

Controlling the end of the cell cycle.

The past year has seen significant advances in our understanding of how the events which occur at the end of mitosis, such as cytokinesis and the inactivation of mitotic cyclin dependent kinases are triggered, and also how they are prevented from occurring prematurely or inappropriately. This control is achieved through a combination of temporally ordered proteolytic events and changes in the subcellular localisation of proteins. These studies have also revealed that the nucleolus and spindle pole bodies play a key role in this regulation.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2000

Proteolysis and the cell cycle: with this RING I do thee destroy.

The ubiquitin system drives the cell division cycle by the timely destruction of numerous regulatory proteins. Remarkably, the two main activities that catalyze substrate ubiquitination in the cell cycle, the Skp1-Cdc53/cullin-F-box protein (SCF) complexes and the anaphase-promoting complex/cyclosome (APC/C), define a new superfamily of E3 ubiquitin ligases, all based on related cullin and RING-H2 finger protein subunits. The circuits that interconnect the SCF, APC/C and cyclin-dependent kinase activities form a master oscillator that coordinates the replication and segregation of the genome.

Anaphase-Promoting Complex-Cyclosome↗
PubMed2000

Sensing and responding to DNA damage.

DNA damage or stalled DNA replication can activate specific signal transduction pathways, termed checkpoints. Checkpoint activation can result in increased repair, induction of a transcriptional programme and inhibition of cell-cycle progression. Recent results have suggested possible mechanisms for the detection of specific DNA structures, provided further information on the organisation of the signal transduction cascade and demonstrated involvement of the checkpoint pathway in DNA repair.

Animals↗
PubMed2000

Cell-cycle checkpoints that ensure coordination between nuclear and cytoplasmic events in Saccharomyces cerevisiae.

Cytoskeletal organization is crucial for several aspects of cell-cycle progression but cytoskeletal elements are quite sensitive to environmental perturbations. Two novel checkpoint controls monitor the function of the actin and microtubule systems in budding yeast and operate to delay cell-cycle progression in response to cytoskeletal perturbations. In cells whose actin cytoskeleton has been perturbed, bud formation is frequently delayed and the morphogenesis checkpoint introduces a compensatory delay of nuclear division until a bud has been formed. In cells whose microtubule cytoskeleton has been perturbed, anaphase spindle elongation often occurs entirely within the mother cell, and the post-anaphase nuclear migration checkpoint introduces a compensatory delay of cytokinesis until one pole of the anaphase nucleus enters the bud. Recent studies indicate that regulators of entry into mitosis are localized to the daughter side of the mother-bud neck whereas regulators of exit from mitosis are localized to the spindle pole bodies. Thus, specific cell-cycle regulators are well-placed to monitor whether a cell has formed a bud and whether a daughter nucleus has been delivered accurately to the bud following mitosis.

Actins↗
PubMed1999

Vitamin K3 induces cell cycle arrest and cell death by inhibiting Cdc25 phosphatase.

Our early reports have indicated that vitamin K3 (VK3) exerts antitumour activity by inhibiting Cdk1 activity and overexpressing the c-myc gene to induce an apoptotic cell death. In the present study, we investigated the effect of VK3 on Cdc25 phosphatase, a Cdk1 activator and c-Myc-downstream protein. Increased protein level but decreased activity of Cdc25A phosphatase was found in cervical carcinoma SiHa cells treated with VK3 for 1 h and allowed to recover for 8, 24, 30 or 45 h. The binding of VK3 to Cdc25 phosphatase was proven by incubating [methyl-3H]-VK3 with the 27 kDa-catalytic domain of Cdc25A phosphatase at 35 degrees C for 2 h. We found that VK3 inhibited cyclin E expression at late G1 phase and cyclin A at G1/S transition of the aphidicolin-synchronised SiHa cells, but had no effect on Cdk2 and Cdk4. The inhibition of cyclins E and A expression was associated with cell cycle progression delay in the S phase. These results indicate that binding of VK3 to the catalytic domain of Cdc25 phosphatase results in the formation of inactive, hyperphosphorylated Cdk1 that subsequently induces cell cycle arrest, leading to cell death. These findings suggest a possible therapeutic strategy, with VK3 serving as a potential antagonist to tumours expressing high levels of proteins containing cysteine such as oncogenic Cdc25A phosphatase.

Apoptosis↗
PubMed2001

Overexpression of aromatase in transgenic male mice results in the induction of gynecomastia and other biochemical changes in mammary glands.

Our previous studies have shown that overexpression of aromatase in mammary glands results in the induction of hyperplastic and dysplastic changes in female transgenic mice. In this study we show that overexpression of aromatase in male transgenic mice results in increased mammary growth and histopathological changes similar to gynecomastia. Increased estrogenic activity also results in an increase in estrogen and progesterone receptor expression in the mammary glands of transgenic males as compared to the nontransgenic males, as well as an increase in the expression of various genes involved in cell cycle and cell proliferation. We have also observed an increase in certain growth factors, such as bFGF and TGFbeta, as a result of aromatase overexpression in the male transgenic mammary glands. In order to obtain a better understanding of the biological significance of gynecomastia, a reliable model is necessary to explain the mechanisms and correlations associated with human cancers. This model, can potentially serve as a predictable and useful tool for studying gynecomastia, hormonal carcinogenesis and action of other carcinogens on hormone induced cancers.

Animals↗
PubMed2000

Activating the DNA damage checkpoint in a developmental context.

BACKGROUND: Studies in unicellular systems have established that DNA damage by irradiation invokes a checkpoint that acts to stall cell division. During metazoan development, the modulation of cell division by checkpoints must occur in the context of gastrulation, differential gene expression and changes in cell cycle regulation. To understand the effects of checkpoint activation in a developmental context, we examined the effect of X-rays on post-blastoderm embryos of Drosophila melanogaster. RESULTS: In Drosophila, DNA damage was previously found to delay anaphase chromosome separation during cleavage cycles that lack a G2 phase. In post-blastoderm cycles that included a G2 phase, we found that irradiation delayed the entry into mitosis. Gastrulation and the developmental program of string (Cdc25) gene expression, which normally regulates the timing of mitosis, occurred normally after irradiation. The radiation-induced delay of mitosis accompanied the exclusion of mitotic cyclins from the nucleus. Furthermore, a mutant form of the mitotic kinase Cdk1 that cannot be inhibited by phosphorylation drove a mitotic cyclin into the nucleus and overcame the delay of mitosis induced by irradiation. CONCLUSIONS: Developmental changes in the cell cycle, for example, the introduction of a G2 phase, dictate the response to checkpoint activation, for example, delaying mitosis instead of or in addition to delaying anaphase. This unprecedented finding suggests that different mechanisms are used at different points during metazoan development to stall cell division in response to checkpoint activation. The delay of mitosis in post-blastoderm embryos is due primarily to inhibitory phosphorylation of Cdk1, whereas nuclear exclusion of a cyclin-Cdk1 complex might play a secondary role. Delaying cell division has little effect on gastrulation and developmentally regulated string gene expression, supporting the view that development generally dictates cell proliferation and not vice versa.

Animals↗