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PubMed2002

An archaebacterial topoisomerase homolog not present in other eukaryotes is indispensable for cell proliferation of plants.

Plants, in contrast to other eukaryotes, possess not only homologs of subunit A (AtSPO11-1, 2, 3) but also of subunit B (AtTOP6B) of the archaebacterial topoisomerase VI. AtTOP6B and AtSPO11-3 are strongly expressed in somatic tissue of Arabidopsis and are able to interact with each other in vitro. A T-DNA insertion in AtTOP6B results in deficient cell proliferation; plants stop growing at the rosette stage, have small crinkled leaves, and die about 4 weeks after germination. Cultured root cells die after a limited number of cell divisions. The mitotic index of the root meristems is strongly reduced. Flow cytometric analysis demonstrates that endoreplication in mutant plants is stopped at the 8C stage; the last cycle is not completed in most cases. Mutant plants show a significant increase in nuclear DNA strand breaks. A T-DNA insertion mutant of AtSPO11-3 has a phenotype that is almost to that of AtTOP6B and the double mutant. Thus, both genes seem to act in vivo as subunits of a functional entity. A loss of this function most likely results in a defect in DNA replication, leading directly, or via the activation of a DNA damage checkpoint, to an arrest of cell division and endoreduplication. The dependence on an archaebacterial topoisomerase VI homolog distinguishes plants from the other eukaryotic kingdoms.

Arabidopsis↗

PubMed2000

Plant cell-size control: growing by ploidy?

The size of plant cells is determined by genetic, structural and physical factors as well as by internal and external signals. Our knowledge of the molecular mechanisms of these controls is still rudimentary. Recent studies indicate that ploidy level exerts an important control on cell size. By increasing ploidy, endoreduplication may allow cells to reach extraordinary sizes. This process is widespread in plants and may provide a means to manipulate the cell volume.

Cell Cycle↗

PubMed2001

A matter of size: developmental control of organ size in plants.

The intrinsic size of plant organs is determined by developmental signals, yet the molecular and genetic mechanisms that control organ size are largely unknown. Ongoing functional analysis of Arabidopsis genes is defining important regulators involved in these mechanisms. Key features of this control are the coordinated activation of growth and cell division by growth regulators and the maintenance of meristematic competence by the ANT gene, which acts as an organ-size checkpoint. Alterations of genome size by polyploidization and endoreduplication can reset this checkpoint by ploidy-dependent, epigenetically regulated differential gene expression. In addition, the regulation of polarized growth and phytohormone signaling also affect final organ size. These findings reveal unique aspects of plant organ-size control that are distinct from animal organ-size control.

Arabidopsis↗

PubMed2001

Chromosomal effects of newly identified water pollutants PBTA-1 and PBTA-2 and their possible mother compounds (azo dyes) and intermediates (non-ClPBTAs) in two Chinese hamster cell lines.

We performed the in vitro micronucleus (MN) test on 2-[2-(acetylamino)-4-[bis(2-methoxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-1) and 2-[2-(acetylamino)-4-[N-(2-cyanoethyl)-ethylamino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-2), which are newly identified water pollutants from the Nishitakase river in Kyoto, Japan, and on their possible mother compounds (AZO DYE) and intermediates (non-ClPBTAs). We tested these compounds in the absence and presence of S9 mix in two Chinese hamster cell lines CHL and V79-MZ and scored MN, polynuclear and karyorrhectic (PN), and mitotic (M) cells. PBTA-2 in the absence of S9 mix induced the strongest responses in both cell lines. It was also a strong inducer of binucleate cells in PN cells in both cell lines, which suggested that it induced polyploidy. PBTA-1 showed clear positive results only in the absence of S9 mix and only in V79-MZ cells, inducing aneuploidy. In CHL cells AZO DYE-1 significantly induced MN cells in the presence of S9 mix, and AZO DYE-2 induced MN and PN cells, including binucleate cells and cells with a multilobed nucleus, in the absence of S9 mix. In V79-MZ cells, AZO DYE-1 and -2 induced primarily M cells in the presence of S9 mix. 9% of the M cells treated with 50 microg/ml AZO DYE-1 showed endoreduplication. AZO DYE-2 at 200 microg/ml condensed the chromatin in 100% of the cells. The non-ClPBTAs were a bit more cytotoxic than the other compounds and induced a slight increase in MN cells in both cell lines. Some of the chemicals tested induced a characteristic karyomorphology that might reflect abnormal cell division. Abnormalities of cell division could be detected in PN and M cells as well as in MN cells. Structure-activity relationships have also been discussed.

Animals↗

PubMed2001

Cytogenetic effects of propyl gallate in CHO-K1 cells.

We investigated whether propyl gallate (PG) can induce sister-chromatid exchanges (SCEs) and chromosomal aberrations (CAs) in CHO-K1 cells. In the absence of an exogeneous metabolizing system, treatments with 0.25-1.5mM PG in plugged flasks for 3h resulted in increases in SCEs, CAs, and endoreduplications (ERDs), which were followed by an increase in the percentage of cells showing cell-cycle delay. At the end of the treatment, a decrease in PG concentration and production of PG dimer and ellagic acid (EA) in the medium were detected, indicating that PG had autoxidized. EA, an oxide of PG, was not genotoxic even at 0.3mM, the maximum concentration soluble in the medium. Several oxygen radical scavengers (superoxide dismutase (SOD), catalase, glutathione and o-phenanthroline (OP)) and an inhibitor of catalase activity (3-amino-1,2,4-triazole (AT)), did not significantly influence PG genotoxicity. When PG autoxidation was suppressed by low pH (6.8) or a 5% CO(2) atmosphere, cell-cycle delay intensified and induction of SCEs and CAs occurred even at the lowest PG dose (0.1mM). When PG (0.5mM) was assayed in the presence of S9 (1.5-9%), gallic acid (GA), a metabolite of PG, was generated in direct proportion to the S9 concentration, while cell-cycle delay and genotoxic effects varied inversely with S9 concentration at the levels over 3%. GA also autoxidized and at >or=0.5mM it induced SCEs. Both catalase and AT suppressed the induction of SCEs by GA or inhibited cell proliferation, indicating that H(2)O(2) participated in the effects. In conclusion, PG in the presence or absence of S9 can induce SCEs, CAs, and ERDs, and the oxides, metabolites and oxygen-free radicals generated during the treatment are partly responsible for these effects.

Amitrole↗

PubMed1998

Differential effects of aneugens and clastogens on incidences of multinucleated cells and of micronucleate cells in Chinese hamster lung (V79) cell line in vitro.

Two aneugens, vinblastine (0.025-0.4 microgram/ml) and colchicine (0.05-0.4 microgram/ml), and two clastogens, mitomycin C (0.05-0.4 microgram/ml) and cyclophosphamide (1-16 micrograms/ml) were applied respectively to the micronucleus test in Chinese hamster lung (V79) cells in vitro, and the frequency of multinucleated cells (Fmu) and that of micronucleate cells (Fmi) in each group were observed. The results showed that at relatively high concentrations, all four agents increased both Fmu and Fmi, but the ratios of Fmu to Fmi in groups of the two aneugens (average of 2.2, 2.8, respectively) were much (10-30 folds) higher than that in groups of the two clastogens (0.09, 0.20). The difference between aneugens and clastogens in the above ratio was much more remarkable than that in areas of micronuclei (only 1.6-2.5 folds for the latter). At relatively low concentrations, the two clastogens increased only Fmi (but not Fmu), while the two aneugens increased only Fmu (but not Fmi). This indicates that the induction of multinuclei by aneugens may be more sensitive than by clastogens, and the induction of micronuclei by clastogens may be more sensitive than by aneugens. So, it is possible for the ratio of Fmu to Fmi to become a simple and sensitive (though indirect) index for distinguishing aneugens from clastogens. Further studies with other mutagens and (or) other cell types will be needed to confirm the deduction. As no difference in frequency of polyploid cells was observed between control group and each treatment, the multinucleation does not seem related to endoreduplication of chromosomes.

Aneuploidy↗

PubMed2000

Quinacrine dihydrochloride, the non-surgical female sterilant induces dicentrics, rings, and marker chromosomes in human peripheral blood lymphocytes treated in vitro: a preliminary report.

During the last decade, quinacrine dihydrochloride (QDH) has been promoted for clinical trials as a much needed non-surgical female sterilant, largely in the Third World. Recently, however, these human trials have come under severe criticism due to lack of adequate evidence of biological safety of QDH, particularly of its genotoxicity in mammalian systems. In the present study, the cytogenetic analysis of QDH-treated human lymphocytes, grown as whole blood cultures in vitro, surprisingly showed a wide range of chromosomal aberrations. At a concentration of 3.0 and 6.0 microg/ml in culture, QDH was cytotoxic, as shown by the very few analyzable metaphases that could be observed. G(0) lymphocytes, treated with 0. 6 microg/ml QDH, exhibited chromosome aberrations including dicentrics, ring configurations, translocations, inversions, and marker chromosomes. Near haploid, polyploid, and endoreduplicated cells were also observed. All the rings appeared to be formed as a result of telomere fusion/association. Twenty percent of the dicentrics observed also indicated telomere fusion/association in the D and G groups of chromosomes. Overall, a frequent involvement of chromosomes 1, 2, and 3 in both unstable and stable chromosome rearrangements was also observed. Exposure of 72-h cultures to 0.45 microg/ml QDH at 69 h resulted in an accumulation of C-metaphases, suggesting that probably QDH behaves as a mitotic spindle inhibitor. The G(2) lymphocytes from two donors exposed to 0.6, 1.5 or 3.0 microg/ml of QDH showed no increase in chromatid aberrations in two donors. However, QDH at 0.6 microg/ml increased the frequency of micronucleated binucleate cells. No increase in sister chromatid exchanges was observed at this concentration. Though preliminary, these observations demonstrate the chromosome damaging ability of QDH in human lymphocytes treated in vitro. Surprisingly, like ionizing radiation, QDH acted by an S-phase-independent mechanism, unlike most of the chemical mutagens. These results warrant detailed investigations on the cytogenetic effects of QDH in vitro, as well as among women exposed to this agent during clinical trials for non-surgical sterilization. The interesting cytogenetic profile of QDH deserves to be pursued and the underlying mechanisms, in particular, the DNA topoisomerase II inhibitory effect, if any, needs to be elucidated.

Adult↗

PubMed2003

Roles of DNA topoisomerases in chromosome segregation and mitosis.

DNA topoisomerases are highly specialized nuclear enzymes that perform topological changes in the DNA molecule in a very precise and unique fashion. Taking into account their fundamental roles in many events during DNA metabolism such as replication, transcription, recombination, condensation or segregation, it is no wonder that the last decade has witnessed an exponential interest on topoisomerases, mainly after the discovery of their potential role as targets in novel antitumor therapy. The difficulty of the lack of topoisomerase II mutants in higher eukaryotes has been partly overcome by the availability of drugs that act as either poisons or true catalytic inhibitors of the enzyme. These chemical tools have provided strong evidence that accurate performance of topoisomerase II is essential for chromosome segregation before anaphase, and this in turn constitutes a prerequisite for the development of normal mitosis. In the absence of cytokinesis, cells become polyploid or endoreduplicated.

Anaphase↗

PubMed1999

Mapping and expression of a bifunctional thymidylate synthase, dihydrofolate reductase gene from maize.

A bifunctional gene (ZmDHFR-TS) encoding dihydrofolate reductase (DHFR) and thymidylate synthase (TS) was cloned from a Zea mays cDNA library. Both of these enzymes are involved in nucleotide biosynthesis, specifically in the formation of thymidine monophosphate (TMP). Comparison of the deduced amino acid sequence with DHFR-TS sequences from three other plant sources revealed over 75% similarity and motifs typical of DHFR-TS proteins. Two copies of the gene were mapped to chromosomes 2 and 4. This represents the first DHFR-TS gene cloned from a monocotyledonous plant. Expression of ZmDHFR-TS was examined in developing kernels and various tissues of maize by RNA gel blot hybridization analysis in order to determine the relationship between expression of this gene and DNA synthesis. RNA transcripts for ZmDHFR-TS accumulated to high levels in developing maize kernels when endosperm cells were undergoing endoreduplication and cell division. Meristematic maize tissues had high levels of ZmDHFR-TS mRNA, but transcripts were barely detectable in RNA isolated from the root elongation zone and from mature leaf tissues.

Amino Acid Sequence↗

PubMed2000

Cell cycle regulation in the course of nodule organogenesis in Medicago.

The molecular mechanisms of de novo meristem formation, cell differentiation and the integration of the cell cycle machinery into appropriate stages of the developmental programmes are still largely unknown in plants. Legume root nodules, which house nitrogen-fixing rhizobia, are unique plant organs and their development may serve as a model for organogenetic processes in plants. Nodules form and are essential for the plant only under limitation of combined nitrogen in the soil. Moreover, their development is triggered by external mitogenic signals produced by their symbiotic partners, the rhizobia. These signals, the lipochitooligosaccharide Nod factors, act as host-specific morphogens and induce the re-entry of root cortical cells into mitotic cycles. Maintenance of cell division activity leads to the formation of a persistent nodule meristem from which cells exit continuously and enter the nodule differentiation programme, involving multiple cycles of endoreduplication and enlargement of nuclear and cell volumes. While the small diploid 2C cells remain uninfected, the large polyploid cells can be invaded and, after completing the differentiation programme, host the nitrogen-fixing bacteroids. This review summarizes the present knowledge on cell cycle reactivation and meristem formation in response to Nod factors and reports on a novel plant cell cycle regulator that can switch mitotic cycles to differentiation programmes.

Cell Cycle↗

PubMed2001

Increasing ploidy level in cell suspension cultures of Doritaenopsis by exogenous application of 2,4-dichlorophenoxyacetic acid.

To clarify the causal factors for ploidy variation in plant cell culture, we attempted to alter ploidy distribution in cell cultures of a tetraploid cultivar of Doritaenopsis by changing the plant growth regulators (PGRs) in the culture medium. The original suspension cultured cells, which had been maintained in medium containing 0.1 mg l-1 1-naphthaleneacetic acid and 1 mg l-1 benzyladenine, were transferred onto various gellan gum solidified media with a single application of PGRs, and the ploidy distributions of the cells were examined using flow cytometry analysis during 3 weeks of culture. Among the PGRs tested, 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-amino-3,5,6-trichloropicolinic acid caused a drastic reduction in the 4C-cell proportion in cell cultures with an increased cell proportion of 8C or higher C-values. In the case of 2,4-D application, a reduction of cell viability was observed. A decreasing proportion was also observed in the 8C-cell population accumulated by 2,4-D treatment, following transfer back to the medium containing the standard PGR composition. These results suggest that the exogenous application of 2,4-D arrested the cell cycle at G2 phase in the Doritaenopsis cells, and the removal of 2,4-D might induce further endoreduplication or recover the mitotic cycle of the G2-arrested cells.

Journal Article↗

PubMed1999

A soybean cDNA encoding a chromatin-binding peptide inhibits mitosis of mammalian cells.

A soybean cDNA encoding the small subunit peptide of a cotyledon-specific 2S albumin (Gm2S-1) is thought to play a role in arresting mitosis during the DNA endoreduplication and cell expansion phase of seed development. The peptide (termed lunasin) contains the cell adhesion motif Arg-Gly-Asp (RGD) followed by eight aspartic acid residues at its C-terminal end. A chimeric gene encoding the lunasin peptide tagged with green fluorescent protein (GFP) arrested cell division, caused abnormal spindle fiber elongation, chromosomal fragmentation, and cell lysis when transiently transfected into murine embryo fibroblast, murine hepatoma, and human breast cancer cells. Deletion of the polyaspartyl end abolished the antimitotic effect. Subcellular localization of lunasin and immunobinding assay using synthetic peptides revealed the preferential adherence of lunasin to chromatin. Immunofluorescence showed that kinetochore proteins were displaced from the centromere in lunasin-transfected cells. These observations suggest that lunasin binds to the chromatin, leading to disruption of kinetochore formation and inhibition of mitosis.

Animals↗

PubMed1985

Fifth Gordon Hamilton-Fairley memorial lecture. Methotrexate resistance and gene amplification: an experimental model for the generation of cellular heterogeneity.

Gene amplification is a mechanism whereby cultured animal cells and human tumours become resistant to cancer chemotherapeutic agents. This review of studies from the authors' laboratory describes properties of the acquisition of resistance to methotrexate in cultured mammalian cells by virtue of amplification of the dihydrofolate reductase gene. These properties result in a heterogeneous cell population with respect to many cell properties, including the number and stability of the amplified genes. Gene amplification results from overreplication of DNA in a single cell cycle as a result of inhibition of DNA synthesis. The cells surviving such overreplication constitute a heterogeneous population with multiple chromosomal changes, including partial or complete endoreduplication of chromosomes, as well as a variety of chromosomal rearrangements. A similar phenomenon may underlie the generation of aneuploidy in tumours, their malignant progression, and the generation of heterogeneity in the tumour cell population.

Animals↗

PubMed1996

Allelic imbalance on chromosome 5q predicts long-term survival in neuroblastoma.

Neuroblastoma is the most common extracranial solid tumour of childhood. Amplification of the proto-oncogene, N-myc, confers a poor prognosis in neuroblastoma, while hyperdiploidy is associated with a favourable outcome. Little is known about the contribution of tumour-suppressor genes to the development or progression of neuroblastoma. We examined allelic imbalance at the locus of the tumour-suppressor gene, APC (adenomatous polyposis coli), on chromosome 5q using a polymerase chain reaction (PCR)-based assay. Nine of 24 (37.5%) informative neuroblastoma tumours showed allelic imbalance (AI) at this locus. Clinical data concerning N-myc amplification and DNA content were correlated with these results in the same patients. Allelic imbalance was found only in tumours containing a single copy of the N-myc gene and exhibiting hyperdiploidy. All nine patients with AI of chromosome 5q were alive after a median follow-up period of 46 months, while 7 of 15 (47%) of those lacking AI at this locus had died (P = 0.018). Allelic imbalance at three additional loci on chromosome 5 was demonstrated in tumours that exhibited AI at the APC locus, suggesting that endoreduplication of chromosome 5 had occurred. Fluorescent in situ hybridisation (FISH) analysis of tumour tissue from one patient exhibiting AI demonstrated two, three, four or six copies of the APC gene per cell, consistent with this hypothesis. These data suggest that allelic imbalance of chromosome 5 is involved in at least a subset of neuroblastomas and influences survival in patients with neuroblastoma.

Alleles↗

PubMed2001

Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression.

The transactivation/transformation-domain associated protein (TRRAP) belongs to the Ataxia-telangiectasia mutated (ATM) super-family and has been identified as a cofactor for c-MYC-mediated oncogenic transformation. TRRAP and its yeast homolog (Tra1p) are components of histone acetyltransferase (HAT) complexes, SAGA (refs. 2,4,5), PCAF (ref. 3) and NuA4 (ref. 6), which are important for the regulation of transcription and cell cycle progression and also have a role in cell viability. Yet the biological function of this molecule and how it controls proliferation are still unclear. Here we show that null mutation of Trrap in mice results in peri-implantation lethality due to a blocked proliferation of blastocysts. We use an inducible Cre-loxP system to show that loss of Trrap blocks cell proliferation because of aberrant mitotic exit accompanied by cytokinesis failure and endoreduplication. Trrap-deficient cells fail to sustain mitotic arrest despite chromosome missegregation and disrupted spindles, and display compromised cdk1 activity. Trrap is therefore essential for early development and required for the mitotic checkpoint and normal cell cycle progression.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Genistein inhibits Brca1 mutant tumor growth through activation of DNA damage checkpoints, cell cycle arrest, and mitotic catastrophe.

Epidemiological studies revealed that amount of consumption of soy was inversely related to incidence of breast cancer. Genistein, the predominant isoflavone in soy, has been reported to reduce the incidence of breast cancer in animal models. To investigate whether genistein has a therapeutic effect on BRCA1-associated breast cancer, we treated Brca1 mutant mammary tumor cells with genistein. We showed that genistein treatment depleted the G1 population of cells, which was accompanied by an accumulation of cells at G2. Some genistein-treated cells entered mitosis; however, they exhibited chromosome abnormalities and maintained tetraploidy owing to abortive mitotic exit. A fraction of G2 cells underwent endoreduplication and became polyploid, which was accompanied by increased cell death through activating DNA damage response. Furthermore, our data indicated that Brca1 mutant cells were more sensitive to genistein than some other types of cancer cells, highlighting a good therapeutic potential of genistein for BRCA1-associated breast cancer.

Animals↗

PubMed2005

The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2-independent roles.

Cyclin E, an activator of phospho-CDK2 (pCDK2), is important for cell cycle progression in metazoans and is frequently overexpressed in cancer cells. It is essential for entry to the cell cycle from G0 quiescent phase, for the assembly of prereplication complexes and for endoreduplication in megakaryotes and giant trophoblast cells. We report the crystal structure of pCDK2 in complex with a truncated cyclin E1 (residues 81-363) at 2.25 A resolution. The N-terminal cyclin box fold of cyclin E1 is similar to that of cyclin A and promotes identical changes in pCDK2 that lead to kinase activation. The C-terminal cyclin box fold shows significant differences from cyclin A. It makes additional interactions with pCDK2, especially in the region of the activation segment, and contributes to CDK2-independent binding sites of cyclin E. Kinetic analysis with model peptide substrates show a 1.6-fold increase in kcat for pCDK2/cyclin E1 (81-363) over kcat of pCDK2/cyclin E (full length) and pCDK2/cyclin A. The structural and kinetic results indicate no inherent substrate discrimination between pCDK2/cyclin E and pCDK2/cyclin A with model substrates.

Amino Acid Sequence↗

PubMed2005

Spotted-dick, a zinc-finger protein of Drosophila required for expression of Orc4 and S phase.

The highly condensed chromosomes and chromosome breaks in mitotic cells of a Drosophila mutant, spotted-dick/pita, are the consequence of defects in DNA replication. Reduction of levels of Spotted-dick protein, by either RNAi or mutation, leads to the accumulation of cells that have DNA content intermediate to 2N and 4N in proliferating tissues and also compromises endoreduplication in larval salivary glands. The Spotted-dick Zinc-finger protein is present in the nuclei of cells committed to proliferation but necessary in cells undertaking S phase. We show that Spotted-dick/Pita functions as a transcription factor and that, in cultured S2 cells, it is an activator of expression of some 30 genes that include the Orc4 gene, required for initiation of DNA replication. Chromatin immunoprecipitation indicates that it associates with the genes that it activates in S2 cells together with other sites that could represent genes activated in other tissues. We discuss the role of Spotted-dick in the coordination of cellular growth and DNA replication.

Animals↗