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PubMed2003

Segmental allopolyploidy and paleopolyploidy in species of Leucaena benth: evidence from meiotic behaviour analysis.

In this paper we report meiotic behaviour in 28 accessions of the tetraploid (2n = 4x = 104 or 112) Leucaena confertiflora, L. diversifolia, L. involucrata, L. leucocephala, L. x spontanea and the diploid (2n = 2x = 52 or 56) L. shannonii and L. macrophylla. We compare and discuss our data with that on literature about polyploidy in the genus. Despite the general predominance of bivalent formation, quadrivalents and other associations were found in all the taxa analysed. In the diploid species. multiple associations were found in up to 62% of the cells in L. shannonii and 97.6% in L. macrophylla. In the tetraploid taxa irregularities such as univalents, trivalents and other multivalents were observed in varying proportions, up to 55% in L. involucrata. Mean meiotic indexes per accession in the diploids and tetraploids were over or near 90%, but pollen fertility varied from 54.2% to 87.3%. The rather frequent presence of quadrivalents in the diploid species supports a paleopolyploid origin. For the tetraploid taxa, the presence of quadrivalents reflect chromosomal homology due to polyploid origin. Even if an autotetraploid origin cannot be ruled out by cytological data alone, considering other existing evidence, it is probable that L. confertiflora, L. pallida, L. leucocephala and L. involucrata are segmental allopolyploids. However, an autopolyploid origin for L. diversifolia cannot be ruled out nor cytologically nor by other existing data.

Crosses, Genetic↗

PubMed1994

The asexual ploidy cycle and the origin of sex.

Sex involves syngamy (gamete fusion), which doubles the amount of DNA in a cell, and meiosis, which halves it. The result is a 'ploidy cycle' of alternating diploid and haploid phases. Asexual reproduction does not require changes of ploidy, and yet asexual forms may have ploidy cycles. Here I show that such cycles lessen the mutation load, compared with permanent diploidy or polyploidy, and are thus likely to evolve in cases where it is always advantageous to have more than one copy of the genome per cell. The asexual ploidy cycle could have facilitated the origin of sex, by providing a means of orderly genetic reduction available immediately after the origin of syngamy.

Animals↗

PubMed1997

Molecular evidence for an ancient duplication of the entire yeast genome.

Gene duplication is an important source of evolutionary novelty. Most duplications are of just a single gene, but Ohno proposed that whole-genome duplication (polyploidy) is an important evolutionary mechanism. Many duplicate genes have been found in Saccharomyces cerevisiae, and these often seem to be phenotypically redundant. Here we show that the arrangement of duplicated genes in the S. cerevisiae genome is consistent with Ohno's hypothesis. We propose a model in which this species is a degenerate tetraploid resulting from a whole-genome duplication that occurred after the divergence of Saccharomyces from Kluyveromyces. Only a small fraction of the genes were subsequently retained in duplicate (most were deleted), and gene order was rearranged by many reciprocal translocations between chromosomes. Protein pairs derived from this duplication event make up 13% of all yeast proteins, and include pairs of transcription factors, protein kinases, myosins, cyclins and pheromones. Tetraploidy may have facilitated the evolution of anaerobic fermentation in Saccharomyces.

Chromosomes, Fungal↗

PubMed1976

Cell kinetics of urethane-induced murine pulmonary adenomata: II, the growth fraction and cell loss factor.

Continuous labelling of urethane induced pulmonary adenomata in adult male A2G mice at intervals up to 20 weeks showed that the growth fraction fell progressively from 18% at 7 weeks to 7% at 20 weeks. This fall appears to be wholly responsible for the decrease in production of adenoma cells with age. A fraction labelled mitoses curve was constructed for pulmonary adenomata at 14 weeks post urethane. Only the first peak was apparent, giving median t2 and ts values of 2 and 9 h respectively. The cell cycle time was calculated at 45 h and the growth fraction at 6-2%, whilst the cell loss factor was estimated at 31%. Other cell loss values were calculated from data on the rate of entry into DNA synthesis obtained previously by double labelling. These values remained constant with time at 83-95%, suggesting that cell loss is in some way linked to cell production. However, the development of polyploidy in adenoma cells could not be eliminated. No areas of necrosis were seen in the adenomata at any time although karyorrhexis occurred in isolated cells. The labelling characteristics of alveolar wall cells in the same lung sections as the adenomata did not vary with time and the continuous labelling curve gave a growth fraction of 1-8%, a DNA synthetic time of 10 h and a cell cycle time of 30 h.

Adenoma↗

PubMed1978

Protein and DNA levels in the submandibular salivary glands of isoproterenol stimulated mice.

The DNA and soluble and sedimental protein levels were studied in isoproterenol stimulated mouse submandibular salivary glands over a period of 200 h. Hypertrophy, the predominant cellular phenomenon following chronic isoproterenol treatment, was associated with a marked elevation of 14C-leucine incorporation into the buffer soluble protein fraction and a less pronounced isotope incorporation into the sedimental sub-cellular fraction as well as continued DNA synthesis. These findings are contrary to the accepted definitions of hypertrophy which preclude continued DNA synthesis. A suggestion is made, therefore, that in the system used the polyploidy associated with the hypertrophy involves.

Animals↗

PubMed2006

The nature of plant species.

Many botanists doubt the existence of plant species, viewing them as arbitrary constructs of the human mind, as opposed to discrete, objective entities that represent reproductively independent lineages or 'units of evolution'. However, the discreteness of plant species and their correspondence with reproductive communities have not been tested quantitatively, allowing zoologists to argue that botanists have been overly influenced by a few 'botanical horror stories', such as dandelions, blackberries and oaks. Here we analyse phenetic and/or crossing relationships in over 400 genera of plants and animals. We show that although discrete phenotypic clusters exist in most genera (> 80%), the correspondence of taxonomic species to these clusters is poor (< 60%) and no different between plants and animals. Lack of congruence is caused by polyploidy, asexual reproduction and over-differentiation by taxonomists, but not by contemporary hybridization. Nonetheless, crossability data indicate that 70% of taxonomic species and 75% of phenotypic clusters in plants correspond to reproductively independent lineages (as measured by postmating isolation), and thus represent biologically real entities. Contrary to conventional wisdom, plant species are more likely than animal species to represent reproductively independent lineages.

Analysis of Variance↗

PubMed1993

Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning.

Defects in nucleotide excision repair are associated with the human condition xeroderma pigmentosum which predisposes to skin cancer. Mice with defective DNA repair were generated by targeting the excision repair cross complementing gene (ERCC-1) in the embryonic stem cell line, HM-1. Homozygous ERCC-1 mutants were runted at birth and died before weaning with liver failure. Examination of organs revealed polyploidy in perinatal liver, progressing to severe aneuploidy by 3 weeks of age. Elevated p53 levels were detected in liver, brain and kidney, supporting the hypothesised role for p53 as a monitor of DNA damage.

Animals↗

PubMed1998

Influence of aminoguanidine on parameters of liver injury and regeneration induced in rats by a necrogenic dose of thioacetamide.

1. When aminoguanidine, a nucleophilic hydrazine compound, was administered to rats (50 mg kg(-1) body wt) 30 min before a necrogenic dose of thioacetamide (500 mg kg(-1) body wt), significant changes related to liver injury and hepatocellular regeneration were observed. 2. The extent of necrosis was noticeably less pronounced, as detected by the peak of serum aspartate aminotransferase activity. Depletion of hepatic glutathione (GSH) and the increase in malondialdehyde concentration as markers of oxidative stress, produced by thioacetamide metabolism, were significantly diminished. However, the activity of microsomal FAD monooxygenase, the system responsible for thioacetamide oxidation, did not show significant alterations. Antioxidant enzyme systems involved in the glutathione redox cycle, such as glutathione reductase and glutathione peroxidase activities, slightly decreased following aminoguanidine pretreatment. 3. Primary cultures of peritoneal macrophages from control rats, when incubated in the presence of serum collected following thioacetamide intoxication, showed a significant decrease in nitric oxide (NO) release at 24 h, that was more pronounced in the group pretreated with aminoguanidine. However, the sharp and progressive increase in macrophage NO release, when incubated in the presence of serum obtained at 48, 72 and 96 h, were increased by aminoguanidine-pretreatment. 4. The cell population involved in DNA synthesis sharply increased in both groups at 48 h of intoxication, although the values at 0, 24, 72 and 96 h were markedly higher in the group pre-treated with aminoguanidine. Polyploidy at 72 and 96 h of intoxication was delayed by the effect of aminoguanidine and a progressive increase in the hypodiploid hepatocyte population, which reached 16% of the total at 96 h, was observed. 5. These results indicate that a single dose of aminoguanidine before thioacetamide administration, markedly diminished the severity of the liver injury by decreasing oxidative stress and lipoperoxidation, but hepatocellular regeneration was apparently unaffected probably due to an enhanced mitogenic activity.

Animals↗

PubMed2003

Function and regulation of Aurora/Ipl1p kinase family in cell division.

During mitosis, the parent cell distributes its genetic materials equally into two daughter cells through chromosome segregation, a complex movements orchestrated by mitotic kinases and its effector proteins. Faithful chromosome segregation and cytokinesis ensure that each daughter cell receives a full copy of genetic materials of parent cell. Defects in these processes can lead to aneuploidy or polyploidy. Aurora/Ipl1p family, a class of conserved serine/threonine kinases, plays key roles in chromosome segregation and cytokinesis. This article highlights the function and regulation of Aurora/Ipl1p family in mitosis and provides potential links between aberrant regulation of Aurora/Ipl1p kinases and pathogenesis of human cancer.

Aneuploidy↗

PubMed2005

Chromosomal stasis versus plasmid plasticity in aphid endosymbiont Buchnera aphidicola.

The study of three genomes of the aphid endosymbiont Buchnera aphidicola has revealed an extraordinary stasis: conservation of gene order and genetic composition of the chromosome, while the chromosome size and number of genes has reduced. The reduction in genome size appears to be ongoing since some lineages we now know to have even smaller chromosomes than the first B. aphidicola analysed. The current sequencing by our group of one of these smaller genomes with an estimated size of 450 kb, and its comparison with the other three available genomes provide insights into the nature of processes involved in shrinkage. We discuss whether B. aphidicola might be driven to extinction and be replaced by secondary aphid endosymbionts. In some lineages, genes encoding key enzymes in the pathways leading to tryptophan and leucine biosynthesis (trpEG and leuABCD, respectively) are located on plasmids, rather than the main chromosome. In contrast to the stasis of the main chromosome, plasmid genes have frequently been transferred to the main chromosome and undergone other gene rearrangements. We propose a two-step scenario to explain these contrasting modes of evolution. Essential genes may have escaped regulation by moving to plasmids in a moving B. aphidicola ancestor. B. aphidicola became polyploidy at a given stage of its evolution and plasmid genes have been transferred to the main chromosome through several independent events.

Animals↗

PubMedDate not supplied

Down-regulation of survivin by antisense oligonucleotides increases apoptosis, inhibits cytokinesis and anchorage-independent growth.

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is detected in most common human cancers but not in adjacent normal cells. Previous studies suggest that survivin associates with the mitotic spindle and directly inhibits caspase activity. To further investigate the function of survivin, we used a survivin antisense (AS) oligonucleotide to downregulate survivin expression in normal and cancer cells. We found that inhibition of survivin expression increased apoptosis and polyploidy while decreasing colony formation in soft agar. Immunohistochemistry showed that cells without survivin can initiate the cleavage furrow and contractile ring, but cannot complete cytokinesis, thus resulting in multinucleated cells. These findings indicate that survivin plays important roles in a late stage of cytokinesis, as well as in apoptosis.

Apoptosis↗

PubMed1997

Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging.

Four INK4 proteins can prevent cell proliferation by specifically inhibiting cyclin D-dependent kinases. Both p18INK4c and p19INK4d were widely expressed during mouse embryogenesis, but p16INK4a and p15INK4b were not readily detected prenatally. Although p15INK4b, p18INK4c and p19INK4d were demonstrated in many tissues by 4 weeks after birth, p16INK4a protein expression was restricted to the lung and spleen of older mice, with increased, more widespread mRNA expression during aging. Transcripts encoding the INK4a alternative reading frame product p19ARF were not detected before birth but were ubiquitous postnatally. Expression of p16INK4a and p15INK4b was induced when mouse embryos were disrupted and cultured as mouse embryo 'fibroblasts' (MEFs). The levels of p16INK4a and p18INK4c, but not p15INK4b or p19INK4d, further increased as MEFs approached senescence. Following crisis and establishment, three of four independently-derived cell lines became polyploid and expressed higher levels of functional p16INK4a. In contrast, one MEF line that sustained bi-allelic deletions of INK4a initially remained diploid. Therefore, loss of p16INK4a and other events predisposing to polyploidy may represent alternative processes contributing to cell immortalization. Whereas p18INK4c and p19INK4d may regulate pre- and postnatal development, p16INK4a more likely plays a checkpoint function during cell senescence that underscores its selective role as a tumor suppressor.

Aging↗

PubMed1998

Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein.

Cell cycle checkpoints and tumor suppressor gene functions appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal destabilization was monitored in relation to telomere structure, lifespan control and G2 checkpoint function. Replicative senescence was inactivated in secondary cultures of human skin fibroblasts by expressing the human papillomavirus type 16 (HPV-16) E6 oncoprotein to inactivate p53. Chromosome aberrations were enumerated during in vitro aging of isogenic control (F5neo) and HPV-16E6-expressing (F5E6) fibroblasts. We found that structural and numerical aberrations in chromosomes were significantly increased in F5E6 cells during aging in vitro and fluorescence in situ hybridization (FISH) analysis using chromosome-specific probes demonstrated the occurrence of rearrangements involving chromosome 4 and 6 in genetically unstable F5E6 cells. Flow cytometry and karyotypic analyses revealed increased polyploidy and aneuploidy in F5E6 cells only at passages > 16, although these cells displayed defective mitotic spindle checkpoint function associated with inactivation of p53 at passages 5 and 16. G2 checkpoint function was confirmed to be gradually but progressively inactivated during in vitro aging of E6-expressing cells. Aging of F5neo fibroblasts was documented during in vitro passaging by induction of a senescence-associated marker, pH 6.0 lysosomal beta-galactosidase. F5E6 cells displayed extension of in vitro lifespan and did not induce beta-galactosidase at high passage. Erosion of telomeres during in vitro aging of telomerase-negative F5neo cells was demonstrated by Southern hybridization and by quantitative FISH analysis on an individual cell level. Telomeric signals diminished continuously as F5neo cells aged in vitro being reduced by 80% near the time of replicative senescence. Telomeric signals detected by FISH also decreased continuously during aging of telomerase-negative F5E6 cells, but telomeres appeared to be stabilized at passage 34 when telomerase was expressed. Chromosomal instability in E6-expressing cells was correlated (P < 0.05) with both loss of telomeric signals and inactivation of G2 checkpoint function. The results suggest that chromosomal stability depends upon a complex interaction among the systems of telomere length maintenance and cell cycle checkpoints.

Cell Line↗

PubMed1999

A p53 and apoptotic independent role for p21waf1 in tumour response to radiation therapy.

Loss of p21 in human cancer cells results in checkpoint failure, induction of polyploidy and subsequent apoptosis following DNA damage. Tumours in immunodeficient mice derived from cells lacking p21 are also more sensitive to ionizing radiation than their wild-type counterparts. Abrogation of p53 in the p21+/+ parental cells results in an in vitro phenotype that is indistinguishable from that of the p21 knockout cells. Thus, the in vitro phenotype resulting from loss of p21 is consistent with its well-established role in the p53/p21 damage response pathway. However, despite the similar in vitro phenotype, p21+/+ cells with abrogated p53 show no evidence of the sensitivity observed in the p21-/- cells when grown as tumours in immunodeficient mice. The increased radio-sensitization stabilization of p21-/- tumours is also unrelated to the increase in apoptosis observed in these tumours following radiation treatment. Apoptosis in the p21-/- tumours was significantly reduced by expression of bcl-2 without any corresponding change in the overall response of the tumour. Similarly, abrogation of p53 in the p21+/+ tumours substantially increased radiation-induced apoptosis within the tumours without increasing their radiation sensitivity. Dissociation of these in vivo and in vitro phenotypes indicates that p21 participates in a novel in vivo specific damage response pathway that is distinct from its role in the p53 pathway, and therefore that it may be an effective therapeutic target for cancer therapy.

Colonic Neoplasms↗

PubMed2002

On the role of aurora-A in centrosome function.

Mammalian aurora-A belongs to a multigenic family of mitotic serine/threonine kinases comprising two other members: aurora-B and aurora-C. In this review we will focus on aurora-A that starts to localize to centrosomes only in S phase as soon as centrioles have been duplicated, the protein is then degraded in early G1. Works in various organisms have revealed that the kinase is involved in centrosome separation, duplication and maturation as well as in bipolar spindle assembly and stability. Aurora kinases are found in all organisms in which their function has been conserved throughout evolution, namely the control of chromosome segregation. In human, aurora-A has focused a lot of attention, since its overexpression has been found to be correlated with the grade of various solid tumours. Ectopic kinase overexpression in any culture cell line leads to polyploidy and centrosome amplification. However, overexpression of aurora-A in particular cell lines such as NIH3T3 is sufficient to induce growth on soft agar. Those transformed cells form tumours when implanted in immunodeficient mice, indicating that the kinase is an oncogene.

Animals↗

PubMed2004

Cyclin E dysregulation and chromosomal instability in endometrial cancer.

Deregulation of cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), has been associated with a broad spectrum of human malignancies. Yet the mechanism linking abnormal cyclin E expression to carcinogenesis is largely unknown. The gene encoding the F-box protein hCdc4, a key component of the molecular machinery that targets cyclin E for degradation, is frequently mutated in endometrial cancer, leading to deregulation of cyclin E expression. Here we show that hCDC4 gene mutation and hyperphosphorylation of cyclin E, a parameter that usually correlates with hCDC4 mutation, have a strong statistically significant association with polypoidy and aneuploidy in endometrial cancer. On the contrary, elevated expression of cyclin E by itself was not significantly correlated with polyploidy or aneuploidy when tumors of similar grade are evaluated. These data suggest that impairment of cell cycle regulated proteolysis of cyclin E may be linked to carcinogenesis by promoting genomic instability.

Cell Cycle↗

PubMed2005

Inhibition of clonogenic tumor growth: a novel function of Smac contributing to its antitumor activity.

While second mitochondria derived activator of caspase (Smac) has been described to sensitize for apoptosis, its effect on cell viability in the absence of apoptotic stimuli has remained unclear. Here, we report that Smac inhibits clonogenic tumor growth by blocking random migration and proliferation and by enhancing apoptosis in a cell density and cell type dependent manner in SH-EP neuroblastoma cells. Inhibition of clonogenic survival by overexpression of full-length or processed Smac strictly depended on low cell density, and was reversible by replatement at high density. We discovered that Smac inhibits cell motility and random migration at low cell density. In addition, Smac enhanced apoptosis and inhibited protein, but not mRNA expression of XIAP, survivin and other short-lived proteins (FLIP, p21), indicating that Smac may globally inhibit protein expression. Also, Smac inhibited proliferation and increased polynucleation with no evidence for polyploidy, cell cycle arrest or senescence indicating that Smac impaired cell division. Interestingly, inhibition of clonogenic capacity by Smac occurred independent of its apoptosis promoting activity. By demonstrating that Smac restrains clonogenic tumor growth, our findings may have important implications for control of tumor growth and/or its metastatic spread. Thus, Smac agonists may be useful in cancer therapy, for example, for tumor control in minimal residual disease. Oncogene (2005) 24, 7190-7202. doi:10.1038/sj.onc.1208876; published online 8 August 2005.

Antibiotics, Antineoplastic↗

PubMed2006

Telomere dysfunction and loss of p53 cooperate in defective mitotic segregation of chromosomes in cancer cells.

Aneuploidy is a fundamental principle of many cancer cells and is mostly related to defects in mitotic segregation of chromosomes. Many solid tumors as well as some preneoplastic lesions have been shown to contain polyploid chromosome numbers. The exact mechanisms behind whole-genome duplications are not known but have been linked to compromised mitotic checkpoint genes. We now report that the telomere checkpoint plays a key role for polyploidy in colon cancer cells. Telomerase suppression by a dominant-negative mutant of hTERT and consecutive telomere dysfunction in wild-type HCT116 colon cancer cells resulted in only minor stable chromosomal alterations. However, higher ploidy levels with up to 350 chromosomes were found when the cell-cycle checkpoint proteins p53 or p21 were absent. These findings indicate that telomere dysfunction in the absence of cell-cycle control may explain the high frequency of alterations in chromosome numbers found in many solid tumors.

Chromosome Segregation↗