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PubMed1983

Chromosomes and causation of human cancer and leukemia. LIII. Comprehensive cytogenetic analysis of an erythroleukemia.

A comprehensive cytogenetic analysis has been performed in a case of erythroleukemia (EL), M6 in the FAB classification. A bone marrow sample was shown to be characterized by an unusually high degree of polyploidy with the presence of a dominating hypotetraploid clone. G-banding analysis revealed extensive structural rearrangements involving chromosomes #1,#3,#12,#16,#17, and #21. The SCE frequency was higher in the cells of the dominant clone when compared to that of near-diploid, presumably nonmalignant cells. Cell cycle analysis revealed that the hypotetraploid cells progressed through the cell cycle much slower than did the near-diploid cells.

Aged↗
PubMed1991

Rare chromosomal aberrations induced by vincristine. Partial endoreduplication and pseudoendoreduplication, segmentally endoreduplicated chromosomes, and segmental premature chromosome condensation.

Vincristine (VCR) is capable of inducing a cell containing both conventional chromosomes (monochromosomes) and diplochromosomes. A total of 124 such metaphases were examined by 5-bromodeoxyuridine (BrdU) incorporation and fluorescence plus Giemsa (FPG) technique to analyze cell cycle kinetics. The majority of cells (119 metaphases) showed differential BrdU incorporation between the two kinds of chromosomes, indicating that partial endoreduplication occurred in these cells. In addition, existence of partially endoreduplicated cells with premature chromosome condensation (PCC) in either mono- or diplochromosomes suggests that the timing of monochromosome-replication was very variable in individual cells. On the other hand, the remaining five metaphases showed that both mono- and diplochromosomes incorporated BrdU similarly, indicating that diplochromosomes are formed by pseudoendoreduplication. Two kinds of chromosomal aberrations probably caused by delay of DNA synthesis on chromosome segments, segmental endoreduplication, and segmental PCC were also reported. Segmental endoreduplication was defined as endoreduplication that occurred on some segments of chromosomes. Out of 119 partially endoreduplicated cells, 3 contained a chromosome consisting of both mono- and diplochromosomal segments, indicating that the former segments missed one round of DNA synthesis. Segmental PCC was defined as PCC restricted to only some segments of chromosomes. Two types of segmental PCC, segmental S-PCC and G2-PCC, were observed in VCR-induced ordinary polyploidy. Although both segmental endoreduplication and segmental PCC occurred with very low frequency, these phenomena suggest that DNA synthesis was disturbed in some part of the nucleus.

Aneuploidy↗
PubMed1986

Herpes simplex virus gene products involved in the induction of chromosomal aberrations.

The effect of short-term herpes simplex virus type 1 (HSV-1) infection on chromosomes of human diploid fibroblasts was examined. In addition to chromosomal breaks, gaps and pulverization, three kinds of cytogenetic damage (double minutes, polyploidy and endoreduplication) not yet reported following productive infection with HSV or other animal viruses were frequently observed. Consistent with previous studies suggesting that the expression of immediate-early and/or early viral gene products is required for the induction of chromosomal damage, was the observation that cells infected at the nonpermissive temperature with HSV-1 temperature-sensitive mutants defective in the gene for the immediate-early transcriptional regulatory protein, ICP4, and three early viral gene products--DNA polymerase (pol), the major HSV DNA-binding protein (ICP8) and an HSV-2 mutant defective in alkaline nuclease--exhibited altered patterns of chromosomal damage relative to the effects of wild-type virus on infected cells. These findings suggest a direct or indirect role for all four gene products in the induction of chromosomal damage. In cells infected with wild-type virus for 4 h or longer, HSV proved to be a more potent mitotic arresting agent than colcemid. Moreover, studies with selected mutants indicate that HSV pol specifically may be involved in mitotic arrest. Additionally, in cells infected at the non-permissive temperature with a pol mutant, the number of polyploid metaphases was reduced 4-fold relative to that seen in wild-type virus-infected cells suggesting a role for HSV pol in the amplification of cellular DNA.

Cell Line↗
PubMed1980

Endopolyploidy in vertebrate liver: an evolutionary perspective.

Hepatocyte nuclei in several species of vertebrates were examined, to establish the frequency of polyploidy and related parameters along evolutionary lines. Nuclei were compared in terms of volume, DNA content, ploidy ranges and internal organization. Several trends emerged. When present, heterochromatin occupied 20--25% of nuclear profile areas, irrespective of nuclear volume and poloidy; the volume of heterochromatin, however, increased in direct proportion to ploidy level. Regardless of internal organization, ploidy and species, a direct correlation emerged between the volumes of nuclei and their absolute DNA content. Results are discussed in terms of structural and genic DNA.

Animals↗
PubMed2006

TPPII promotes genetic instability by allowing the escape from apoptosis of cells with activated mitotic checkpoints.

Overexpression of TPPII correlates with accelerated growth and the appearance of centrosome and chromosome aberrations, suggesting that the activity of this enzyme may be critical for the induction and/or maintenance of genetic instability in malignant cells. We now find that the length of mitosis and of the entire cell cycle is significantly reduced in TPPII overexpressing HEK293 cells compared to untransfected and control transfected cells. Functional TPPII knockdown by shRNA interference caused a significant slowdown in cell growth and the accumulation of cells that delayed or failed to complete mitosis. TPPII overexpressing cells evade mitotic arrest induced by spindle poisons and display high levels of polyploidy despite the constitutively high expression of major components of the spindle checkpoint. TPPII overexpression correlated with upregulation of IAPs and with resistance to mitochondria dependent apoptosis induced by p53 stabilization. Thus, TPPII appears to promote malignant cell growth by allowing exit from mitosis and the survival of cells with severe mitotic spindle damage.

Aminopeptidases↗
PubMed2006

The synthesis and SAR of 2-amino-pyrrolo[2,3-d]pyrimidines: a new class of Aurora-A kinase inhibitors.

A new class of Aurora-A inhibitors have been identified based on the 2-amino-pyrrolo[2,3-d]pyrimidine scaffold. Here, we describe the synthesis and SAR of this novel series. We report compounds which exhibit nanomolar activity in the Aurora-A biochemical assay and are able to inhibit tumor cell proliferation. This study culminates in compound 30, an inhibitor with potent activity against Aurora A (IC50=0.008 microM), anti-proliferative activity against several tumor cell lines and induces polyploidy in H460 cells.

Antineoplastic Agents↗
PubMed2005

Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction.

OBJECTIVE: Although the genetic program for reinitiating DNA synthesis exists in post-mitotic cardiomyocytes, and it was reported that in human acute myocardial infarction (AMI) a significant proportion of myocytes enter mitosis, the rule is that the lost tissue is replaced by a collagen scar. The purpose of this study was to search for the basis of this discordance in order to devise future strategies to induce division of myocytes into daughter cells that may replace the lost tissue with contractile cells. METHODS: In 15 human hearts with 1- to 21-day-old infarcts, the expression of the cell cycle proteins Ki67 antigen, cyclins D, A, and B1, the presence of mitotic bodies, and the ploidy status were investigated with immunoenzymatic methods, light and laser confocal microscopy, and densitometry in the myocytes surrounding the infarct area. RESULTS: In 7- to 13-day-old infarcts, 11.61+/-6.94% of the myocytes presented Ki67+ nuclei, and a lower proportion presented cyclins D, A, and B. At earlier and later times, the proportion of Ki67+ myocytes was significantly lower. Although under confocal microscopy and fluorescent labels, some of the Ki67+ myocytes appeared to be in different stages of mitosis, with Nomarski optics and hematoxylin counterstaining, the condensed chromosomes, although arranged in metaphase and anaphase plates or split in sister chromatids, were always located within a preserved nuclear envelope, indicating the presence of endomitosis. Conventional mitosis was exceptionally observed. In the 14- and 21-day-old infarcts, the ploidy of the myocytes adjacent to the infarct was significantly higher than in distant zones. CONCLUSION: These observations indicate that in human infarcts, entrance of cardiomyocytes into the cell cycle is transient and that endomitosis, leading to polyploidy, rather than mitosis, leading to karyokinesis, is the final fate of cycling cells. Both observations may account for the discordance between the regenerative ability of myocytes and the lack of an efficient reparative process in human AMI.

Adult↗
PubMed2005

Neosis--a paradigm of self-renewal in cancer.

We recently described a novel form of cell division termed neosis, which appears to be the mode of escape of cells from senescence and is involved in the neoplastic transformation and progression of tumors (Cancer Biol & Therap 2004;3:207-18). Neosis is a parasexual somatic reduction division and is characterized by (1) DNA damage-induced senescence/mitotic crisis and polyploidization, (2) followed by production of aneuploid daughter cells via nuclear budding, (3) asymmetric cytokinesis and cellularization conferring extended, but, limited mitotic life span to the offspring, and (4) is repeated several times during tumor growth. The immediate neotic progeny are termed the Raju cells, which seem to transiently display stem cell properties. The Raju cells immediately undergo symmetric mitotic division and become mature tumor cells. Exposure of tumor cells to genotoxic agents yields neosis-derived Raju cell progenies that are resistant to genotoxins, thus contributing to the recurrence of drug-resistant tumor growth. Similar events have been described in the literature under different names through several decades, but have been neglected due to the lack of appreciation of the significance of this process in cancer biology. Here we review and interpret the literature in the light of our observations and the recent advances in self-renewal in cancer. Neosis paradigm of self-renewal of cancer growth is consistent with the telomere attrition, aging and origin of cancer cells after reactivation of telomerase, and constitutes an alternative to the cancer stem cell hypothesis. We summarize the arguments favoring Raju cells and not cancer stem cells, as the source of self-renewal in cancer and present a comprehensive hypothesis of carcinogenesis, encompassing various aspects of cancer biology including senescence, tumor suppressor genes, oncogenes, cell cycle checkpoints, genomic instability, polyploidy and aneuploidy, natural selection, apoptosis, endoapoptosis, development of resistance to radiotherapy and chemotherapy leading tumor progression into malignancy.

Cell Death↗
PubMed2005

Mitotic catastrophe and endomitosis in tumour cells: an evolutionary key to a molecular solution.

Following genotoxic insult, p53 mutated tumour cells undergo mitotic catastrophe. This is characterised by a switch from mitosis to the endocycle. The essential difference between mitosis and the endocycle is that in the latter, DNA synthesis is uncoupled from cell division, which leads to the formation of endopolyploid cells. Recent data suggests that a return from the endocycle into mitosis is also possible. Furthermore, our observations indicate that a particular type of endocycle known as endomitosis may be involved in this return. Here we review the role of endomitosis in the somatic reduction of polyploidy during development and its postulated role in the evolution of meiosis. Finally, we incorporate these evolutionary data to help interpret our most recent observations in the tumour cell system, which indicate a role for endomitosis and meiotic regulators, in particular p39mos in the segregation of genomes (somatic reduction) of these endopolyploid cells.

Animals↗
PubMed2005

Endopolyploidy as a morphogenetic factor of development.

This paper summarizes the works published by author and his co-workers in the Russian journal Tsitologiya concerning endopolyploidy in mollusks and appraises this phenomenon in general. Both ontogenetic and phylogenetic aspects of endopolyploidy have been studied. In the snail Succinea lauta, a complex examination of endomitosis has been performed. A regular replacement of the normal (complete) proliferative mitosis by abnormal (incomplete) restitutional mitosis, and then by Geitler's classic endomitosis has been demonstrated. We examined 29 bivalve and 82 gastropod species for the presence of polyploid cells in glandular tissues and ganglia. In the bivalve species, ordinary diploid cells form various tissues, while in the gastropods, the role of polyploidy in tissue development appears to increase in phylogenesis. The rise of endopolyploidy and cell giantism in histogeneses of a variety of animal and plant species is widely known. It is believed to be a regular event in the evolution of certain groups. To give a universal interpretation of endopolyploidy, we proposed that a single polyploid cell be better considered as an endoclone. In this case, evolutionary transformation of diploid cell clones into polyploid endoclones may be viewed as Dogel's oligomerization applied to cell-tissue level. From this viewpoint, major properties of an oligomerized system (intensification of function, functional efficiency (ergonomy), increased genomes reliability, simplification of the intra- and supersystem regulations, and acceleration of development) can be considered as principal peculiarities of polyploid growth strategy. The above peculiarities allow one to consider endopolyploidy as an additional means of integrative onto(histo)genetic regulations and correlations and as an important evolutionary factor (coordinations) acting through natural selection. Thus, in general, endopolyploidy is an adaptive morphogenetic factor, but its concrete role may differ in different tissues and organisms depending on cell specialization and histogenetic particularities.

Animals↗
PubMed2004

Comparative genome analysis of monocots and dicots, toward characterization of angiosperm diversity.

The importance of angiosperms to sustaining humanity by providing a wide range of 'ecosystem services' warrants increased exploration of their genomic diversity. The nearly completed sequences for two species representing the major angiosperm subclasses, specifically the dicot Arabidopsis thaliana and the monocot Oryza sativa, provide a foundation for comparative analysis across the angiosperms. The angiosperms also exemplify some challenges to be faced as genomics makes new inroads into describing biotic diversity, in particular polyploidy (genome-wide chromatin duplication), and much larger genome sizes than have been studied to date.

Arabidopsis↗
PubMed2006

Polyploid hybrids: multiple origins of a treefrog species.

Hyla versicolor, a tetraploid treefrog, is reported to have originated via multiple hybridization events involving three diploid ancestors. Its complex reticulate history provides insights into the roles that polyploidy and hybridization can play in the origin of species.

Animals↗
PubMed2005

Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase.

We investigated why treatment of cells with dual aurora A and B kinase inhibitors produces phenotypes identical to inactivation of aurora B. We found that dual aurora kinase inhibitors in fact potently inhibit cellular activities of both kinases, indicating that inactivation of aurora B bypasses aurora A in mitosis. RNAi experiments further established that inactivation of aurora B indeed bypasses the requirement for aurora A and leads to polyploidy. Inactivation of aurora A activates checkpoint kinase BubR1 in an aurora B-dependent manner. Our results thus show that aurora B is responsible for mitotic arrest in the absence of aurora A.

Aurora Kinase B↗
PubMed2005

Thioredoxin overexpression in HT-1080 cells induced cellular senescence and sensitization to gamma radiation.

An increment of thioredoxin-1 (TRX) is observed in many human primary cancers and appears to contribute to an increase of cell growth and a resistance to chemotherapy. On the contrary, when TRX was overexpressed in the HT-1080 fibrosarcoma cells, the cell growth was retarded and chromosomal polyploidy and cellular senescence were induced. TRX-overexpression made HT-1080 cells resistant to an oxidative stress caused by H2O2 or paraquat. But these cells were significantly sensitive to ionizing radiation, showing an abrogation of the G2 checkpoint. Their DNA contents were twice of the controls and they expressed typical senescence markers. Their expression levels of p53 and cyclin-dependent kinase inhibitors (CDKI) were about 2-3-fold higher than the control. Nevertheless, cyclin D1 and D3, which are negatively regulated by CDKIs, were also increased. Overall, in HT-1080 cells the TRX-overexpression created a state of cellular senescence caused by a simultaneous stimulation of the mitogen-activated pathways and an inhibition of the cyclin-dependent kinases, which is known as a hypermitogenic arrest.

Blotting, Western↗
PubMed2006

Cisplatin-induced endoreduplication in CHO cells: DNA damage and inhibition of topoisomerase II.

It has been proposed that polyploid cells that arise during a variety of pathological conditions and as a result of exposure to genotoxicants, typically in the liver, become aneuploid through genetic instability. Aneuploidy contributes to, or even drives, tumour development. We have assessed the capacity of the drug cisplatin, one of the most commonly used compounds for the treatment of malignancies, to induce endoreduplication, a particular type of polyploidy, in cultured Chinese hamster AA8 cells. Taking into account that any interference with DNA topoisomerase II (topo II) function leads to endoreduplication, we have found that treatment of the cells with this platinum compound results in a dose-dependent inhibition of the catalytic activity of the enzyme. These observations are discussed on the basis of a possible dual action of cisplatin leading to a combined negative effect on normal segregation of chromosomes. On the one hand, through the drug capacity to efficiently inhibiting the catalytic activity of topo II itself and, on the other hand, as a consequence of changes in DNA such as base modifications and cross-links that result from cisplatin treatment, likely leading to a lack of recognition/binding of DNA by the enzyme. These observations support a model in which the involvement of topo II in different pathways leading to induced endoreduplication has been proposed, and seem to bear significance as to the possible origin of the development of secondary tumours as a result of cisplatin treatment of primary malignancies.

Aneugens↗
PubMed2006

Assessment of genotoxicity of 14 chemical agents used in dental practice: ability to induce chromosome aberrations in Syrian hamster embryo cells.

To assess the genotoxicity of 14 chemical agents used as locally applied agents in dental practice, the ability of these agents to elicit chromosome aberrations was examined using Syrian hamster embryo (SHE) cells. Chromosome aberrations in SHE cells were induced by treatment with three of eight chemical agents used as endodontic medicaments, i.e. ethylenediaminetetraacetic acid (EDTA), formocresol (a mixture of formalin and tricresol), and sodium arsenite. The other five chemical agents, i.e. chloramphenicol, p-chlorophenol, p-phenolsulfonic acid, sodium hypochlorite, and tetracycline hydrochloride exhibited a negative response for chromosome aberrations. Assessment of three dyes used for disclosing dental plaque showed chromosome aberrations induced by basic fuchsin but not by acid fuchsin and erythrosine B. Three local anesthetics, lidocaine hydrochloride, prilocaine hydrochloride, and procaine hydrochloride, were negative for chromosome aberrations. Among the ten chemical agents that exhibited a negative response in the assay, p-chlorophenol, sodium hypochlorite, and erythrosine B induced chromosome aberrations in SHE cells when treated in the presence of exogenous metabolic activation. The percentages of cells with polyploidy or endoreduplication were enhanced by formocresol, sodium arsenite, p-chlorophenol, p-phenolsulfonic acid, sodium hypochlorite, erythrosine B, prilocaine hydrochloride, and procaine hydrochloride in the absence or presence of exogenous metabolic activation. Our results indicate that the chemical agents that had a positive response in the present study are potentially genotoxic to mammalian cells.

Anesthetics↗
PubMed2005

Few polyploid blastomeres in morphologically superior bovine embryos produced in vitro.

Morphologically inferior bovine embryos developed in vivo have been shown by karyotyping to have a higher rate of chromosomally abnormal cells than morphologically normal embryos. The objective of this study was to re-examine this finding using interphase cytogenetics. A total of 155 IVP Day 8 bovine blastocysts were graded by their morphology (excellent, good, or poor) and timing of development (hatched, expanded, or non-expanded), and afterwards analysed for chromosome abnormalities by fluorescence in situ hybridization using differentially labelled probes for chromosomes 6 and 7. The overall frequency of diploid embryos was 7%, and did not differ according to grading. Although the frequency of mixoploidy was not correlated to the morphological grading, the blastocysts with excellent morphology displayed fewer polyploid nuclei in comparison to blastocysts with good (P=0.05) or poor morphology (P=0.01). There were however also prominent exceptions showing that a blastocyst with an excellent morphology can display a high degree of polyploidy. The results further demonstrate that the morphologically normal embryos contain a higher number of cells and develop more rapidly than the morphologically inferior embryos.

Animals↗
PubMed2006

Poorly known relatives of Arabidopsis thaliana.

Non-model Arabidopsis species have been widely used as outgroup taxa in studies of molecular evolution. In Arabidopsis lyrata, Arabidopsis halleri and Arabidopsis arenosa, traits pertaining to self-incompatibility, heavy metal tolerance and inter-specific hybridization have been subjected to detailed genetic analysis. However, the full potential for exploring the causes and consequences of natural variation in complex traits within the genus Arabidopsis has not been widely appreciated or realized. Here, we draw on broadly dispersed information to characterize the basic biology, ecology, population genetics and molecular evolution for these three non-model Arabidopsis species. We illustrate how the wealth of functional and genomic tools pioneered in A. thaliana can be applied to gain insights into adaptive evolution of ecologically important traits and genome-wide processes, such as polyploidy, speciation and reticulate evolution, within and among Arabidopsis species.

Arabidopsis↗