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PubMed1997

Aneugenic activity in human cultured lymphocytes. An overall study with colchicine using the micronucleus assay and fluorescence in situ hybridization techniques.

The effects induced by aneugenic agents on chromosome segregation are manifold. The biological relevance of these effects has led to the development of assays specifically detecting aneugens. In this context, the micronucleus (MN) assay in binucleated human lymphocytes along with FISH has been considered a pertinent tool for detecting aneugenic and clastogenic activity. However, the MN assay is insensitive in detecting aneugenic effects other than chromosome loss. By using the aneugenic model compound colchicine and X chromosome centromere-specific FISH, we have shown that besides chromosome loss in binucleated cells, other effects such as MN in mononucleated cells, cells arrested at metaphase, polyploidy and non-disjunction are also consistently induced by aneugenic agents. A chromosome 1 centromeric probe was used simultaneously with X chromosome centromeric labeling in mononucleated cells in order to distinguish polysomy from polyploidy. It is concluded that all these effects should be considered for a comprehensive evaluation of aneugenic activity.

Adult↗
PubMed2000

Nucleotide excision repair gene (ERCC1) deficiency causes G(2) arrest in hepatocytes and a reduction in liver binucleation: the role of p53 and p21.

A wide range of DNA lesions, both UV and chemically induced, are dealt with by the nucleotide excision repair (NER) pathway. Defects in NER result in human syndromes such as xeroderma pigmentosum (XP), where there is a 1000-fold increased incidence of skin cancer. The ERCC1 protein is essential for NER, but ERCC1 knockout mice are not a model for XP. In the absence of exogenous DNA-damaging agents, these mice are runted and die before weaning, with dramatically accelerated liver polyploidy and elevated levels of p53. Here we present a morphological, immunological, and molecular study to understand the mechanism for the unusual liver pathology in ERCC1-deficient mice. We show that the enlarged ERCC1-deficient hepatocytes are arrested in G(2) and that DNA replication and the normal process of binucleation are both reduced. This is associated with a p53-independent increase in expression of the cyclin-dependent kinase inhibitor p21. The most dramatic feature of the ERCC1-deficient liver phenotype, the accelerated polyploidy, is not rescued by p53 deficiency, but we show that p53 is responsible for the reduced DNA replication and binucleation. We consider that the liver phenotype is a response to unrepaired endogenous DNA damage, which may reflect an additional non-NER-related function for the ERCC1 protein.

Animals↗
PubMed1996

Expression of Bcl-xL and loss of p53 can cooperate to overcome a cell cycle checkpoint induced by mitotic spindle damage.

During somatic cell division, faithful chromosomal segregation must follow DNA replication to prevent aneuploidy or polyploidy. Damage to the mitotic spindle is one potential mechanism that interferes with chromosomal segregation. The accumulation of aneuploid or polyploid cells resulting from a disrupted mitotic spindle is presumably prevented by cell cycle checkpoint controls. In the course of studying cells that overexpress the apoptosis-inhibiting protein Bcl-xL, we found that these cells have an increased rate of spontaneous tetraploidization, suggesting that apoptosis may play an important role in eliminating cells that fail to complete mitosis properly. When cells expressing Bcl-xL are treated with mitotic spindle inhibitors, a significant percentage reinitiate DNA replication and become polyploid. Nevertheless, the majority of cells expressing Bcl-xL undergo a prolonged p53-dependent cell cycle arrest following mitotic spindle damage. Unexpectedly, p53 expression is not induced in mitosis, nor does it influence M-phase arrest. Instead, cells with mitotic spindle damage only transiently arrest in M phase, and despite failing to complete mitosis, appear to proceed to G1. During this subsequent growth factor-dependent phase, p53 is induced and mediates cell cycle arrest. In cells that do not overexpress Bcl-xL, elimination of the p53-dependent growth arrest with a dominant negative mutant also results in polyploidy after mitotic spindle damage, but under these conditions most cells die by apoptosis. Expression of Bcl-xL and abrogation of p53 cooperate to allow rapid and progressive polyploidization following mitotic spindle damage. Our results suggest that suppression of apoptosis by bcl-2-related genes and loss of p53 function can act cooperatively to contribute to genetic instability.

Apoptosis↗
PubMed2006

Widespread genome duplications throughout the history of flowering plants.

Genomic comparisons provide evidence for ancient genome-wide duplications in a diverse array of animals and plants. We developed a birth-death model to identify evidence for genome duplication in EST data, and applied a mixture model to estimate the age distribution of paralogous pairs identified in EST sets for species representing the basal-most extant flowering plant lineages. We found evidence for episodes of ancient genome-wide duplications in the basal angiosperm lineages including Nuphar advena (yellow water lily: Nymphaeaceae) and the magnoliids Persea americana (avocado: Lauraceae), Liriodendron tulipifera (tulip poplar: Magnoliaceae), and Saruma henryi (Aristolochiaceae). In addition, we detected independent genome duplications in the basal eudicot Eschscholzia californica (California poppy: Papaveraceae) and the basal monocot Acorus americanus (Acoraceae), both of which were distinct from duplications documented for ancestral grass (Poaceae) and core eudicot lineages. Among gymnosperms, we found equivocal evidence for ancient polyploidy in Welwitschia mirabilis (Gnetales) and no evidence for polyploidy in pine, although gymnosperms generally have much larger genomes than the angiosperms investigated. Cross-species sequence divergence estimates suggest that synonymous substitution rates in the basal angiosperms are less than half those previously reported for core eudicots and members of Poaceae. These lower substitution rates permit inference of older duplication events. We hypothesize that evidence of an ancient duplication observed in the Nuphar data may represent a genome duplication in the common ancestor of all or most extant angiosperms, except Amborella.

Cycadopsida↗
PubMed1977

Fertilization and preimplantation development in vitro of mouse eggs obtained following stimulation with different doses of pregnant mare serum: a comparison of the responses in two strains.

Unfertilized eggs were recovered from TO and (C57BL/10 X CBA)F1 females, induced to ovulate with 0.75--10.0 IU PMS and 5.0 IU HCG/mouse, and mixed with TO sperm in vitro. Among the groups of F1 eggs, there were no significant differences in either fertilization or development to the blastocyst stage in vitro. With TO eggs, however, there was significantly lower fertility in the 0.74 and 1.5 IU PMS groups than in the higher PMS dose groups. Conversely, preimplantation development was significantly better withe low doses. To determine whether polyploidy migh affect viability in vitro, digynic polyploidy was experimentally induced in both F1 and TO eggs with cytochalasin B. Development of polyploid F1 X TO embryos to the blastocyst stage did not differ significantly form that of untreated embryos. Development of polyploid TO X TO embryos obtained from eggs stimulated with 1.5 IU PMS was still higher than that for eggs stimulated with 7.5 IU PMS. This suggests that cytoplasmic inadequacies, rather than genome imbalance, are responsible for the reduced ability of the eggs stimulated with high doses of PMS to reach the blastocyst stage in vitro.

Animals↗
PubMed1989

Cytofluorometric determination of nuclear DNA in heart muscles of patients with muscular dystrophy.

The degree of DNA-polyploidy of cardiac muscle cells was investigated by cytofluorometry in 4 cases of progressive muscular dystrophy (DMP) and 2 cases of myotonic dystrophy (DM), and the results were compared with those for non-dystrophic hearts of normal or increased weight. The heart muscle cells from all patients with these forms of dystrophy showed marked nuclear DNA hyperploidy reaching 16c, irrespective of cardiac hypertrophy or atrophy. In the non-dystrophic group, DNA hypertrophy corresponding to that of dystrophy was only detected in cases of marked cardiac hypertrophy exceeding a weight of 400 g. The wasting of the respiratory musculature, deformity of the thorax and cardiac muscular atrophy appeared to be the principal factors causing DNA polyploidy in patients with muscular dystrophy.

Adolescent↗
PubMed2006

The role of hybridization, polyploidization and glaciation in the origin and evolution of the apomictic Ranunculus cassubicus complex.

The Ranunculus cassubicus complex, comprising diploids and polyploids, is a good model for studying the role of hybridization and polyploidy in the origin of apomixis. Results from amplified fragment length polymorphism (AFLP) and simple sequence repeat (SSR) analyses performed on 448 individuals were combined with evidence from morphology, isozymes, karyology and distribution. Our results indicated a unique hybrid origin for the apomictic hexaploid R. carpaticola from north-western Slovakia, involving two sexual parents: autotetraploid R. cassubicifolius from the northern pre-Alps, and diploid R. carpaticola from central Slovakia. The hybrids were intermediate to the parents, but unique alleles have resulted from genomic reorganisation in the allopolyploids, which might also have triggered apomixis. Their distribution patterns and estimated ages suggest that hybridization may be correlated with the last glacial period. Hybridization seems to be the major origination for apomicts in the R. cassubicus complex. Polyploidy creates novel sexual genotypes and acts as a springboard for the production of new hybrids, but it only results in a combination with hybridization in apomixis. In turn, asexuality has permitted the perpetuation and establishment of ecologically divergent hybrid genotypes.

Alleles↗
PubMed1975

A quantitative study of the second meiotic metaphase in male mice (Mus musculus).

Over 11,000 second meiotic metaphase spreads stained for the pericentromeric region have been studied quantitatively in male mice of 14 strains. The sex-chromosome constitution of a cell could be judged objectively if X and Y chromosomes and ploidy were all scored. A bias arose if only Y chromosomes and ploidy were scored but could be corrected statistically. There was no sign of other forms of bias. The original contiguity of X and Y second metaphases in vivo was very occasionally evident in the preparations. Most of the subhaploid aneuploid counts were assumed to be artifactual. The incidence of truly aneuploid second metaphases in 13 strains was estimated as 0.38+/-0.12%. The estimated average rate per chromosome was 0.019+/-0.006%, with a comparable order of magnitude for the sex chromosomes alone. Simultaneous aneuploidy of two or more chromosomes of the haploid set was estimated to be very rare. Of the spreads from 13 strains, 9.6% were polyploid (2N, 3N, 4N) and showed most of the possible combinations of sex chromosomes. Nearly all the polyploid spreads were considered to arise by artifactual cell fusion at the time of second metaphase during the preparative technique, especially of the X and Y daughter-cell products of the first meiotic division. Other modes of origin (true polyploidy, accidental superposition of cells during preparation) were unlikely. The data could be accommodated by a statistical model with only four parameters. It allowed for artifactual fusion mainly between daughter cells but also between non-daughter cells, bias in one scoring method, and bias in the numbers of cells with given ploidy successfully mounted. Current techniques of chromosome preparation were thought to be wholly unsuitable for the recognition of true polyploidy. The artifactual origin of polyploid spreads was borne out by an absence of polyploid spermatozoa in 14 strains. There appeared to be a virtually constant transmission rate of paternal X and Y chromosomes from early meiosis to late blastocyst. The estimated rate of 49.05+/-0.67% with a Y chromosome also estimated the primary sex ratio. There was evidence of polymorphism in autosomal pericentromeric staining in 3 strains. No measure of the numbers of autosomes or sex chromosomes varied significantly between duplicate preparations or between duplicate males of a strain.

Aneuploidy↗
PubMed2004

Megakaryocytes express functional Aurora-B kinase in endomitosis.

Endomitosis (EnM) in megakaryocytes (MKs) is characterized by abortion of mitosis in late anaphase and failure of cytokinesis; subsequent reinitiation of DNA synthesis results in polyploidy. Ablation of chromosomal passenger proteins including Aurora-B kinase causes defects in late anaphase and cytokinesis in diploid cells; thus one hypothesis is that the expression or function of these proteins in polyploid MKs is abnormal. It has been reported that Aurora-B kinase mRNA is decreased in polyploid megakaryocytic cells, suggesting that deficiency of Aurora-B kinase is responsible for EnM. We examined the localization of Aurora-B kinase and additional members of the chromosomal passenger protein and aurora kinase families in MKs. We found that in EnM MKs (1) Aurora-B kinase is present and appropriately localized to centromeres in early EnM; (2) in low-ploidy human MKs, centromeric localization of survivin and inner centromere protein (INCENP) can also be demonstrated; (3) the function of Aurora-B kinase, as measured by Ser10 phosphorylation of histone H3, is intact; and (4) aurora-A kinase localizes appropriately to centrosomes in EnM. These results suggest that EnM MKs appropriately express functional Aurora-B kinase and related proteins in early anaphase, making a simple deficiency of this protein an unlikely explanation for polyploidy in this cell type.

Anaphase↗
PubMed2006

Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe.

BACKGROUND: We have previously reported that p53 mutated radioresistant lymphoma cell lines undergo mitotic catastrophe after irradiation, resulting in metaphase arrest and the generation of endopolyploid cells. A proportion of these endopolyploid cells then undergo a process of de-polyploidisation, stages of which are partially reminiscent of meiotic prophase. Furthermore, expression of meiosis-specific proteins of the cancer/testis antigens group of genes has previously been reported in tumours. We therefore investigated whether expression of meiosis-specific genes was associated with the polyploidy response in our tumour model. METHODS: Three lymphoma cell lines, Namalwa, WI-L2-NS and TK6, of varying p53 status were exposed to a single 10 Gy dose of gamma radiation and their responses assessed over an extended time course. DNA flow cytometry and mitotic counts were used to assess the kinetics and extent of polyploidisation and mitotic progression. Expression of meiotic genes was analysed using RT-PCR and western blotting. In addition, localisation of the meiotic cohesin REC8 and its relation to centromeres was analysed by immunofluorescence. RESULTS: The principal meiotic regulator MOS was found to be significantly post-transcriptionally up-regulated after irradiation in p53 mutated but not p53 wild-type lymphoma cells. The maximum expression of MOS coincided with the maximal fraction of metaphase arrested cells and was directly proportional to both the extent of the arrest and the number of endopolyploid cells that subsequently emerged. The meiotic cohesin REC8 was also found to be up-regulated after irradiation, linking sister chromatid centromeres in the metaphase-arrested and subsequent giant cells. Finally, RT-PCR revealed expression of the meiosis-prophase genes, DMC1, STAG3, SYCP3 and SYCP1. CONCLUSION: We conclude that multiple meiotic genes are aberrantly activated during mitotic catastrophe in p53 mutated lymphoma cells after irradiation. Furthermore, we suggest that the coordinated expression of MOS and REC8 regulate the extent of arrested mitoses and polyploidy.

Blotting, Western↗
PubMed2003

p53 deficiency and defective mitotic checkpoint in proliferating T lymphocytes increase chromosomal instability through aberrant exit from mitotic arrest.

During the proliferation of T cells for successful immune responses against pathogens, the fine regulation of cell cycle is important to the maintenance of T cell homeostasis and the prevention of lymphoproliferative disorders. However, it remains to be elucidated how the cell cycle is controlled at the mitotic phase in proliferating T cells. Here, we show that during the proliferation of primary T cells, the disruption of the mitotic spindle leads to cell-cycle arrest at mitosis and that prolonged mitotic arrest results in not only apoptosis but also the form of chromosomal instability observed in human cancers. It is interesting that in response to spindle damage, the phosphorylation of BubR1, a mitotic checkpoint kinase, was significantly induced in proliferating T cells, and the expression of the dominant-negative mutant of BubR1 compromised mitotic arrest and subsequent apoptosis and thus led to the augmentation of polyploidy formation. We also show that in response to prolonged spindle damage, the expression of p53 but not of p73 was significantly induced. In addition, following sustained mitotic arrest, p53-deficient T cells were found to be more susceptible to polyploidy formation than the wild type. These results suggest that during flourishing immune response, mitotic checkpoint and p53 play important roles in the prevention of chromosomal instability and in the maintenance of the genomic integrity of proliferating T cells.

Animals↗
PubMed2003

Targeted expression of calmodulin increases ventricular cardiomyocyte proliferation and deoxyribonucleic acid synthesis during mouse development.

The cell signaling pathways that control ventricular cardiomyocyte proliferation during development are poorly understood. Here we show that increasing levels of the ubiquitous Ca(2+) receptor calmodulin (CaM) can regulate cardiomyocyte proliferation in vivo. Targeted overexpression of calmodulin in the heart during embryonic development leads to a 37% or a 79% increase in the number of ventricular myocytes present at embryonic d 17 in mice heterozygous or homozygous for the transgene, respectively. Whereas all homozygous mice die within 10 d after birth, most of the heterozygous mice survive even though they contain 40% more ventricular myocytes relative to the wild-type mice throughout development and into adulthood. The CaM transgene continues to be overexpressed postnatally and, although cell proliferation ceases soon after birth, the elevated levels of CaM lead to an increase in DNA synthesis, which correlates with an increase in the degree of ventricular myocyte polyploidy. Only after proliferation has ceased and polyploidy has become maximal does the continued presence of overexpressed CaM lead to ventricular hypertrophy. However, unlike the case for myocyte number, turning off expression of the CaM transgene results in regression of the hypertrophic response. Together, our results reveal that excess CaM enhances the extent of cell proliferation and DNA synthesis as well as development of hypertrophy of ventricular myocytes in vivo, in a manner consistent with the normal timing of these events during heart development.

Animals↗
PubMed1997

Different manner of DNA synthesis in polyploidizations of meth-A and B16F10 cell lines.

Polyploidization of Meth-A and B16-F10 cells by demecolcine was examined using flow cytometry (FCM). In the presence of demecolcine, both cell lines were polyploidized to more than 16c DNA content. A marked difference was observed in the durations of S phase of polyploidy. The S-phase duration of Meth-A cells was doubly increased with ploidy, but that of B16F10 cells remained constant. When the rate of DNA synthesis in the polyploidizing cells was examined through the BrdU-uptake experiments, it was confirmed that the level of DNA-synthesis rate was constant in Meth-A cells but increased in B16F10 cells. The cellular content of c-Myc protein in polyploidized cells was also examined using anti-c-Myc monoclonal antibody. The c-Myc level of Meth-A cells was constant regardless of the ploidy but that of B16F10 cells increased with ploidy. Thus, the c-Myc content seems to be related to the duration of S phase in polyploidy.

Animals↗
PubMed2005

Evidence for high frequency of chromosomal mosaicism in spontaneous abortions revealed by interphase FISH analysis.

Numerical chromosomal imbalances are a common feature of spontaneous abortions. However, the incidence of mosaic forms of chromosomal abnormalities has not been evaluated. We have applied interphase multicolor fluorescence in situ hybridization using original DNA probes for chromosomes 1, 9, 13, 14, 15, 16, 18, 21, 22, X, and Y to study chromosomal abnormalities in 148 specimens of spontaneous abortions. We have detected chromosomal abnormalities in 89/148 (60.1%) of specimens. Among them, aneuploidy was detected in 74 samples (83.1%). In the remaining samples, polyploidy was detected. The mosaic forms of chromosome abnormality, including autosomal and sex chromosomal aneuploidies and polyploidy (31 and 12 cases, respectively), were observed in 43/89 (48.3%) of specimens. The most frequent mosaic form of aneuploidy was related to chromosome X (19 cases). The frequency of mosaic forms of chromosomal abnormalities in samples with male chromosomal complement was 50% (16/32 chromosomally abnormal), and in samples with female chromosomal complement, it was 47.4% (27/57 chromosomally abnormal). The present study demonstrates that the postzygotic or mitotic errors leading to chromosomal mosaicism in spontaneous abortions are more frequent than previously suspected. Chromosomal mosaicism may contribute significantly to both pregnancy complications and spontaneous fetal loss.

Abortion, Spontaneous↗
PubMed2000

Vascular beta-adrenoceptor function in hypertension and in ageing.

Functional beta-adrenoceptors (beta-AR) have been identified and characterized in blood vessels under in vivo conditions as well as in vascular smooth muscle cells (SMC) grown in culture. Agonist occupancy of beta-AR activates adenylyl cyclase (AC) via the stimulatory guanine nucleotide-binding protein (Gs) and leads to elevations in intracellular adenosine 3'5'-cyclic monophosphate levels (cAMP). Increased cAMP activates the cAMP-dependent protein kinase (PKA), with subsequent phosphorylation of various target proteins. This beta-AR pathway interacts with several other intracellular signalling pathways via cross-talk, so that activation by beta-AR agonists may also modulate other second messengers and protein kinases. SMC beta-AR play an important role in SMC function. In intact blood vessels they mediate SMC relaxation by various intracellular mechanisms, ultimately causing a decrease in intracellular Ca2+ levels. In cultured SMC, activation of the beta-AR pathway results in inhibition of cellular proliferation, the development of SMC polyploidy, and SMC apoptosis. Blood vessels from hypertensive animals are characterized by an increase in SMC cell mass, a greater incidence of SMC polyploidy in the aorta, and an impairment in the beta-agonist-mediated SMC relaxation. Some of these changes may result from an attenuation of beta-AR function due to agonist-induced receptor desensitization caused by the uncoupling of receptors from the Gs-AC system. The phosphorylated beta-AR may in turn trigger new signals and activate different intracellular pathways. However, the details of these mechanisms are still unresolved. Since functional beta-AR play such a prominent and multi-faceted role in SMC function, it is important to understand how these diverse physiological effects are mediated by this receptor system, and how they contribute to the development of hypertension. With ageing, a decrease in beta-AR-Gs-AC coupling is observed, and this is implicated in the reduced responsiveness of SMC. The similarities in SMC beta-AR functional changes in hypertension and in ageing suggest that the underlying mechanisms are also analogous.

Age Factors↗
PubMed2002

Cassava, Manihot esculenta Crantz, genetic resources: origin of the crop, its evolution and relationships with wild relatives.

About 98 species of Manihot are known. All of them are native to the New World and are concentrated in four regions in Brazil and Central America. All the Manihot species so far examined have 2n = 36 chromosomes. Interspecific hybrids between cassava and its wild relatives show relatively normal meiosis, and further generations can be obtained. Electrophoresis shows affinity among wild species of different sections, and between some of them and cassava. Both polyploidy and apomixis may have contributed to speciation in this genus. Polyploidy produced genetic variability, while apomixis is responsible for perpetuating new hybrid types adapted to different environments. Cassava may have originated by hybridization between two wild Manihot species, followed by vegetative reproduction of the hybrid.

Biological Evolution↗
PubMed1992

[Ploidies of cardiomyocytes in human myocardial hypertrophy].

DNA cytophotometry has been performed in ventricular cardiomyocytes of hypertrophic human hearts. In the cases of hypertrophy in adults (generalized atherosclerosis, postinfarct scars), polyploidy expression did not exceed the limits of normal variability developed during childhood. In the cases of hypertrophy caused by congenital heart defects, high polyploidy has been revealed (the mean level 20c and more, where c is haploid DNA content), which considerably exceeded the upper limit of normal variability (approximately 10c). Our hypothesis has confirmed that heart hypertrophy in adults proceeds in conditions of stable genome rather than due to redundant polyploidization of the ventricular myocytes. The same idea assumes enhanced polyploidization of the myocytes in childhood in humans with congenital heart diseases.

Adult↗
PubMedDate not supplied

[Role of non-radiation factors in forming cytogenetic effects in evacuees from a 30-km zone of the Chernobyl Nuclear Power Plant].

The time-effect relationship for chromatid type aberrations, chromosome type fragments, hyperploidy and polyploidy levels in peripheral blood lymphocytes were investigated in inhabitants of t. Pripiat' and nearby villages, who were departured from the Chernobyl NPP 30-km exclusive zone during first days after the Chernobyl catastrophe. The time-course changes of the mentioned cytogenetic indices in evacuees were displayed as a gradual decline of chromosomal rearrangements and genome abnormality frequencies from the statistically elevated level in the first 1-2 years after the accident to the subcontrol meanings at the end of the 14-years observation period. In early terms after exposure the frequency of chromatid exchanges in adult men and the polyploidy level in women aged 23-35 years were sufficiently increased comparing with other evacuee subgroups. Some peculiarities of the fragment aberration frequency dynamics were shown for persons with different terms of the departure from the Chernobyl zone. The role of the combination of mutagenic factors acted in the accidental situation at Chernobyl for inducing the elevated level of cytogenetic damage in evacuees is discussed.

Adolescent↗