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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↗

PubMed1984

Induction of endoreduplication by hydrazine in Chinese hamster V 79 cells and reduced incidence of sister chromatid exchanges in endoreduplicated mitoses.

Hydrazine in high concentrations very effectively induces endoreduplication in Chinese hamster V79 cells. The addition of 5-bromodeoxyuridine (BrdU) for the duration of one cell cycle prior to the induction of endoreduplication produces diplochromosomes with sister chromatid differentiation (SCD) after differential chromatid staining. The fact that diplochromosomes with complete SCD are obtained shows that endoreduplication was induced in cells that were in G2-phase. The analysis of sister chromatid exchanges (SCEs) showed that hydrazine treatment rarely led to increased SCE frequencies in mitoses after endoreduplication, but that it caused a strong SCE induction in diploid second division metaphases in the same culture. Neither catalase nor cysteine had an effect on the induction of endoreduplication or the incidence of SCEs. Treatment of the cells with mitomycin C prior to addition of BrdU led to increased SCE frequencies. Compared with the normal mitoses from the same preparation, the mitoses after endoreduplication showed a significantly reduced induction of SCEs. In contrast to these findings, SCE induction was not reduced in the common tetraploid V 79 cells after colcemid-induced polyploidization.

Animals↗

PubMed1983

Studies on endoreduplication. III. Endoreduplication induced by mitomycin C in PHA-stimulated tonsillar lymphocyte cultures.

The activity of mitomycin C (MMC) to induce endoreduplication was examined in PHA-stimulated tonsillar lymphocyte cultures. Cellular kinetics of both diploid and endoreduplicated cells was studied by the combined techniques of thymidine and BrdU incorporation. The kinetic data showed that the increase of endoreduplicated cells induced by MMC correlated with the increase of the second-generation diploid cells. Also, it showed that the majority of endoreduplicated cells found at the time when the maximal number of endoreduplicated cells was obtained had incorporated BrdU only once into their diplochromosomes. This suggests that MMC-induced endoreduplicated cells originate from MMC-induced G2-arrested cells.

Cells, Cultured↗

PubMed1981

Studies on endoreduplication. II. Spontaneous occurrence and cellular kinetics of endoreduplication in PHA-stimulated tonsillar lymphocytes.

Cells with spontaneously endoreduplicated chromosomes were observed in tonsillar lymphocyte cultures from the second to the seventh day of culture, although at a low frequency. Cell cycle kinetics leading to endoreduplication were examined by the 5-bromodeoxyuridine (BrdU)-acridine orange method. The diplochromosomes showed four fluorescent patterns depending on the period during which BrdU was incorporated into the DNA. The kinetic data also revealed two populations among the cells with endoreduplicated chromosomes: one with a shorter (36 or 48 h) and the other with a longer cell cycle time. The existance of the latter population was shown by the fact that cell without differentially stained chromatids were observed many hours after BrdU addition (up to 120 h). This suggests that some cells with endoreduplicated chromosomes originate from cells arrested in G2.

Aneuploidy↗

PubMed1985

Cytogenetic demonstration of out-of-phase DNA synthesis in endoreduplicated CHO cells: evidence for partial endoreduplication.

Out-of-phase DNA synthesis, which is demonstrated cytogenetically as premature chromosome condensation (PCC), was analyzed in endoreduplicated Chinese hamster ovary (CHO) cells induced by colchicine or vincristine. Like conventional polyploid cells, endoreduplicated cells exhibited PCC in either S or G2. The former was more frequently observed in drug-treated cultures. In addition to these two types of PCC, other mitotic figures showing out-of-phase DNA synthesis were found. Such cells contained both conventional chromosomes (monochromosomes) and diplochromosomes. Differential FPG staining of chromatids in these cells showed that diplochromosomes incorporated BrdU twice while monochromosomes did so once, indicating the occurrence of partial endoreduplication in one of the sister nuclei of multinucleate cells. The possible mechanisms underlying induction of out-of-phase DNA synthesis and production of partial endoreduplication are discussed.

Animals↗

PubMedDate not supplied

Distribution of diploidy, polyploidy, and endoreduplication in fra(X) positive and negative lymphocytes, amniocytes, and chorionic villi.

Expression of fragile X [fra(X)] (q27.3) and endoreduplicated metaphases have been reported in methotrexate-treated (MTX) fra(X) cultures (Kerem B, Biotein R, Schaap T [1988]: Chromosoma 97: 6-10). Further, new data (Kimchi-Sarfaty C, Goitein R, Kerem B, Werner M, Medan B, Schaap T [1991]: Am J Med Genet, this issue) indicate that MTX may specifically induce polyploidy and endoreduplication in cells with the fra(X) mutation. To confirm and extend these results, we have studied short-term lymphocyte cultures incubated in M199, a folate deficient system, and RPMI-1640 in the presence and absence of 5-fluorodeoxyuridine (FUdR) exposure during the last day of a 4 day culture. No endoreduplicated cells were seen under these conditions and there was no change in the level of polyploidy. We also studied the distribution of polyploid and endoreduplicated cells in amniotic fluid and chorionic villus sample cultures from one fra(X) positive and 4 at-risk specimens. No increase in the incidence of polyploidy or endoreduplication was observed in cultures exposed to MTX for both 24 and 48 hours from a fra(X) positive amniotic fluid case. Cytogenetic results were fra(X) negative for the remaining 4 cases tested. There was significant discordance between our findings and those expected based on MTX-induced increased frequencies of polyploidy and endoreduplication. Thus, our studies do not confirm the reported correlation between the presence of FRAXA and increased frequencies of polyploidy and endoreduplication in MTX-exposed amniocyte cultures and there was no evidence for increased levels of polyploidy and endoreduplication in short-term fra(X) lymphocyte cultures exposed to non-MTX fra(X) induction.

Amniotic Fluid↗

PubMed1999

Gibberellin and ethylene control endoreduplication levels in the Arabidopsis thaliana hypocotyl.

We have previously shown that endoreduplication levels in hypocotyls of Arabidopsis thaliana (L.) Heynh. are under negative control of phytochromes. In this study, the hormonal regulation of this process was analysed using a collection of A. thaliana mutants. The results show that two hormones in particular, gibberellin (GA) and ethylene, play distinct roles. Hypocotyl cells of the GA-deficient mutant ga1-11 grown in the dark did not elongate and showed a greatly reduced endoreduplication. Normal endoreduplication could be restored by supplying 10(-9) M of the gibberellin GA(4+7), whereas the restoration of normal cell growth required 100-fold higher concentrations. The GA-insensitive mutant gai showed reduced cell elongation but normal ploidy levels. We conclude that (i) GA(4+7) has a global positive effect on endoreduplication and (ii) that endoreduplication is more sensitive to GA(4+7) than cell elongation. Ethylene had a completely different effect. It induced an extra round of endoreduplication both in light- and dark-grown seedlings and acted mainly on discrete steps rather than having a global effect on endoreduplication. The genes EIN2 and CTR1, components of the ethylene signal transduction pathway were both involved in this process.

Arabidopsis↗

PubMed1981

The mechanisms of endoreduplication.

Chinese hamster cells, Don line, were treated with concanavalin A (ConA), calcium ionophore A23187 (A23187), colchicine, sodium fluoride (NaF), 6-thiopurine, dibutyryl cyclic AMP (db-cAMP), and other nucleotides, alone or in combination. A23187 itself did not induce endoreduplication but did so in combination with ConA. NaF could induce endoreduplication and the combination of NaF and ConA showed a synergistic effect. db-cAMP suppressed the inducing activity of ConA. The findings that various chemicals are inducers of endoreduplication and that synergistic effects appear on combined treatments suggest that various mechanisms of induction of endoreduplication may exist. The chemical nature of the inducers and the suppressor, db-cAMP, implies that blocking of the phosphorylation of some cellular components may be involved as a main mechanism. Analysis of the endoreduplication cell cycle indicated that cells treated with reagents in S require a longer cell cycle than those treated in G2 and that the length of the lag period between induction treatment and the initiation of S, the length of S, and the length of G2 war variable. The inducers, induction mechanisms, and the cell cycle of endoreduplication seem to vary; however, the essence of endoreduplication is the omission of mitotic events by connecting S and G1.

Aneuploidy↗

PubMed2002

Genetic analyses of endoreduplication in Zea mays endosperm: evidence of sporophytic and zygotic maternal control.

Flow cytometry was used to assess the variability of endoreduplication in endosperms of maize inbred lines. Little variation was found between midwestern dent types, and high levels of endoreduplication were observed in popcorns. Endoreduplication is different between inbred lines by 13-18 days after pollination, and flow cytometric analysis of ploidy level was feasible until 20 DAP. To study the genetic regulation of endoreduplication, four inbreds were crossed to B73 and developing endosperms from both parental, reciprocal F(1), and backcross generations were subjected to flow cytometric analysis. Three measurements of endoreduplication were calculated from these data and analyzed as quantitative genetic traits. Multiple models of trait inheritance were considered including triploid, diploid, sporophytic maternal, and maternal and paternal zygotic nuclear inheritance. Maternal zygotic effects, often considered a form of parental imprinting, and maternal sporophytic effects were detected. To test the feasibility of introgressing a high endoreduplication phenotype into a midwestern dent inbred line, a backcross population was generated from B73 x Sg18. Parental and progeny endoreduplication levels were compared and heritabilities assessed. The heritabilities calculated from these data generally agree with the values calculated in the larger crossing experiments.

Analysis of Variance↗

PubMed2001

Water deficit inhibits cell division and expression of transcripts involved in cell proliferation and endoreduplication in maize endosperm.

Water deficit at the early post-pollination stage in cereal grains decreases endosperm cell division and, in turn, decreases the capacity for storage material accumulation. Post-mitotic replication of nuclear DNA (endoreduplication) may also play a role in stress effects. To gain a better understanding of the extent to which cell proliferation and endoreduplication are affected by water deficit, nuclear numbers and size were examined in endosperms of maize (Zea mays L.) by flow cytometry and the transcript levels of genes which have recognized roles in the cell cycle were quantified. Water deficit from 5-13 d after pollination (DAP) decreased the rate of endosperm cell division by 90% and inhibited [3H]-thymidine incorporation into DNA from 9-13 DAP. The proportion of nuclei engaging in endoreduplication and nuclear DNA content increased steadily from 9-13 DAP in controls, but water deficit initially increased the proportion of endoreduplicating nuclei at 9 DAP, then halted further entry into endoreduplication and S-phase cycling from 9-13 DAP. Transcript levels of alpha-tubulin, and the S-phase gene products histone H3 and PCNA were not affected by water deficit until 13 DAP, whereas those of ZmCdc2, a cyclin dependent kinase (CDK) with regulatory roles in mitosis, were inhibited substantially from 9-13 DAP. Cell proliferation and associated processes were inhibited at initial stages of the stress episode, whereas endoreduplication and associated S-phase processes were not inhibited until the stress was more advanced. It was concluded that endosperm mitosis has greater sensitivity than endoreduplication to water deficit.

Adaptation, Physiological↗

PubMed2002

Endoreduplication is not inhibited but induced by aphidicolin in cultured cells of tobacco.

Endoreduplication is a common process in plants that allows cells to increase their DNA content. In the tobacco cell cultures studied in this work it can be induced by simple hormone deprivation. Mesophyll protoplast-derived cells cultured in the presence of NAA (auxin) and BAP (cytokinin) keep on dividing, while elongation and concomitant DNA endoreduplication are induced and maintained in a medium containing only NAA. If aphidicolin is given to the two types of culture, no effect is observed on elongating, endoreduplicating cells. However, the cells programmed for division switch to elongation and DNA endoreduplication. Thus aphidicolin, an inhibitor of the replicative DNA polymerases, alpha and delta, does not inhibit endoreduplication, and furthermore actually induces it when the mitotic cell cycle is blocked. DNA duplication and cell growth can only be completely blocked if ddTTP, an inhibitor of DNA polymerase-beta, is given together with aphidicolin. This result implies that an aphidicolin-resistant DNA polymerase, such as the repair-associated DNA polymerase-beta, can mediate DNA synthesis during endoreduplication and can substitute for polymerases-alpha and -delta when the latter are inhibited. Similar results are obtained in cultures of the BY-2 cell line by withdrawing auxins from the culture medium. In this cell line endoreduplication is induced only in a small proportion of the cells. A greater proportion of the cells are blocked in the G(2) phase of the cell cycle.

Aphidicolin↗

PubMed2004

A dominant negative mutant of cyclin-dependent kinase A reduces endoreduplication but not cell size or gene expression in maize endosperm.

Cells in maize (Zea mays) endosperm undergo multiple cycles of endoreduplication, with some attaining DNA contents as high as 96C and 192C. Genome amplification begins around 10 d after pollination, coincident with cell enlargement and the onset of starch and storage protein accumulation. Although the role of endoreduplication is unclear, it is thought to provide a mechanism that increases cell size and enhances gene expression. To investigate this process, we reduced endoreduplication in transgenic maize endosperm by ectopically expressing a gene encoding a dominant negative mutant form of cyclin-dependent kinase A. This gene was regulated by the 27-kD gamma-zein promoter, which restricted synthesis of the defective enzyme to the endoreduplication rather than the mitotic phase of endosperm development. Overexpression of a wild-type cyclin-dependent kinase A increased enzyme activity but had no effect on endoreduplication. By contrast, ectopic expression of the defective enzyme lowered kinase activity and reduced by half the mean C-value and total DNA content of endosperm nuclei. The lower level of endoreduplication did not affect cell size and only slightly reduced starch and storage protein accumulation. There was little difference in the level of endosperm gene expression with high and low levels of endoreduplication, suggesting that this process may not enhance transcription of genes associated with starch and storage protein synthesis.

Cell Cycle↗

PubMed1999

p21(Waf1/Cip1) inhibition of cyclin E/Cdk2 activity prevents endoreduplication after mitotic spindle disruption.

During a normal cell cycle, entry into S phase is dependent on completion of mitosis and subsequent activation of cyclin-dependent kinases (Cdks) in G1. These events are monitored by checkpoint pathways. Recent studies and data presented herein show that after treatment with microtubule inhibitors (MTIs), cells deficient in the Cdk inhibitor p21(Waf1/Cip1) enter S phase with a >/=4N DNA content, a process known as endoreduplication, which results in polyploidy. To determine how p21 prevents MTI-induced endoreduplication, the G1/S and G2/M checkpoint pathways were examined in two isogenic cell systems: HCT116 p21(+/+) and p21(-/-) cells and H1299 cells containing an inducible p21 expression vector (HIp21). Both HCT116 p21(-/-) cells and noninduced HIp21 cells endoreduplicated after MTI treatment. Analysis of G1-phase Cdk activities demonstrated that the induction of p21 inhibited endoreduplication through direct cyclin E/Cdk2 regulation. The kinetics of p21 inhibition of cyclin E/Cdk2 activity and binding to proliferating-cell nuclear antigen in HCT116 p21(+/+) cells paralleled the onset of endoreduplication in HCT116 p21(-/-) cells. In contrast, loss of p21 did not lead to deregulated cyclin D1-dependent kinase activities, nor did p21 directly regulate cyclin B1/Cdc2 activity. Furthermore, we show that MTI-induced endoreduplication in p53-deficient HIp21 cells was due to levels of p21 protein below a threshold required for negative regulation of cyclin E/Cdk2, since ectopic expression of p21 restored cyclin E/Cdk2 regulation and prevented endoreduplication. Based on these findings, we propose that p21 plays an integral role in the checkpoint pathways that restrain normal cells from entering S phase after aberrant mitotic exit due to defects in microtubule dynamics.

CDC2-CDC28 Kinases↗

PubMed2006

Endoreduplication of human smooth muscle cells induced by 2-methoxyestradiol: a role for cyclin-dependent kinase 2.

Endoreduplication has been suggested to contribute to the development of hypertrophy of smooth muscle cells (SMCs) in hypertension. However, endoreduplication in vascular SMCs and the underlying molecular mechanisms are not clear. Treatment of human SMCs with 10 microM 2-methoxyestradiol (2-ME) for 24 h induces accumulation of cells with > or =4N DNA content, and some polyploid/aneuploid cells actively synthesize their DNA, suggesting the occurrence of endoreduplication. In addition, 2-ME treatment upregulates the expression of cyclin-dependent kinase 2 (Cdk2). The present study was designed to characterize endoreduplication of human SMCs and explore the potential roles of Cdk2 in endoreduplication induced by 2-ME. Treatment with 2-ME (10 microM) for 2-4 days not only caused increases in >4N cells and their reentry into S phase but also induced overduplication of chromosomes. Furthermore, 2-ME increased the kinase activity of Cdk2 and its interaction with cyclin E. Inducible overexpression of dominant-negative Cdk2 in human SMCs inhibited both DNA synthesis of >4N cells and the accumulation of >4N cells induced by 2-ME. We conclude that 2-ME induces endoreduplication of human SMCs and Cdk2 plays an important role in endoreduplication in response to 2-ME.

2-Methoxyestradiol↗

PubMed2006

The Aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function.

VX-680 is a potent inhibitor of Aurora kinases that induces the accumulation of cells with > or =4N DNA content, followed by cell death. Here, we define the role of p53 and p21(Waf1/Cip1) in cell cycle perturbations following exposure to VX-680. Endoreduplication and apoptosis in response to VX-680 are limited in A549 and MCF-7 cells expressing wild-type p53, and markedly enhanced in cells lacking p53, including those engineered to express the HPV16-E6 oncoprotein or short interfering RNA pools targeting p53. In contrast, endoreduplication and apoptosis occur in the p53 wild-type cell lines, RKO and U2OS. The difference in response to VX-680 among these cell lines correlates with the timing of induction of p21(Waf1/Cip1) and its ability to inhibit cyclin E-cdk2 activity. In A549 cells, VX-680 induces the expression of p53 and p21(Waf1/Cip1) within 24 hours, with consequent inhibition of cyclin E-cdk2, and reduction of retinoblastoma protein phosphorylation, limiting endoreduplication. In RKO and U2OS cells, the induction of p21(Waf1/Cip1) is delayed and associated with higher residual cyclin E-cdk2 kinase activity and retinoblastoma protein phosphorylation, followed by progressive endoreduplication and apoptosis. Abrogation of p21(Waf1/Cip1) expression by short interfering RNA targeting in A549 cells results in a substantial increase in the degree of endoreduplication, whereas inducible expression of p21(Waf1/Cip1) in p53-negative NCI-H1299 cells inhibits VX-680-induced endoreduplication and cell death. These data suggest that the integrity of the p53-p21(Waf1/Cip1)-dependent postmitotic checkpoint governs the response to Aurora kinase inhibition. Although cells with intact checkpoint function arrest with 4N DNA content, those with compromised checkpoint function are more likely to undergo endoreduplication followed by eventual apoptosis.

Apoptosis↗

PubMed1985

Do the frequencies of sister chromatid exchanges in endoreduplicated mitoses provide a measure for lesion persistence and repair?

Endoreduplication was induced in V 79 cells using Colcemid. The concentration of Colcemid necessary to induce endoreduplication is about 1000 times higher than that needed to arrest mitoses or to induce ordinary tetraploid cells. Diplochromosomes with sister chromatid differentiation were obtained by adding BrdU for the duration of one cell cycle prior to the induction of endoreduplication. The induction of endoreduplication with Colcemid had no influence on the frequency of sister chromatid exchanges (SCEs). Treating the cultures with mitomycin C (MMC) before adding BrdU increased the percentage of endoreduplicated mitoses and also led to marked SCE induction. In the diplochromosomes, the frequencies of both twin SCEs (first cycle) as well as single SCEs (second cycle) were increased. It was also found that the SCE frequencies in mitoses after endoreduplication were lower than the values found in diploid and ordinary tetraploid metaphases of the same preparation. The possible conclusions concerning the lifetime of SCE-inducing lesions and the influence of repair processes are discussed.

Animals↗

PubMed1976

Effects of actinomycin D and puromycin on colchicine-induced endoreduplication in Chinese hamster cells in vitro.

Experiments were carried out to study the events through which the process of endoreduplication occurs after treatment with colchicine in Chinese hamster cells cultivated in vitro, and to analyse the differences between the processes leading to normal mitosis and those leading to endoreduplication. Chinese hamster cells (line C-125) were treated with colchicine (10(-4) M) for 1 h, in order to induce endoreduplication. Before and after colchicine treatment the cultures were treated at various intervals with actinomycin D and puromycin. For preparation of mitosis specific RNA synthesis is required, and also synthesis of a specific protein, which is not required for endoreduplication. Moreover this suggests not only that the cells that endoreduplicate do not need new RNA and protein synthesis, but that inhibition of their synthesis apparently favours the processes of endoreduplication.

Cell Division↗

PubMed2002

Ectopic B-type cyclin expression induces mitotic cycles in endoreduplicating Arabidopsis trichomes.

Cell differentiation is frequently accompanied by a switch from a mitotic division cycle to an endoreduplication cycle. In endoreduplicating cells, DNA synthesis continues in the absence of cell divisions, and it is speculated that endoreduplication represents a shortened mitotic division cycle. In animals, it has been shown that cells switching from mitotic to endoreduplication cycles continue to express factors controlling the G1-S transition, whereas the transcription of mitotic factors controlling the G2-M transition is negatively regulated. It is unknown how the mitotic factors are repressed and what the functional significance of their suppression is. To test the function of two mitotic cyclins in an endoreduplication cycle, we expressed CYCLIN B1;1 and CYCLIN B1;2 in unicellular Arabidopsis trichomes. During wild-type development, trichomes undergo an average of four endoreduplication cycles, leading to a DNA content of approximately 32C. We find that ectopic expression of CYCLIN B1;2, not CYCLIN B1;1, induces mitotic divisions resulting in multicellular trichomes. The CYCLIN B1;2-triggered cell divisions appeared normal with respect to both nuclear division and cytokinesis. We show that CYCLIN B1;2 is misexpressed in the siamese mutant, which also produces multicellular trichomes. Additional overexpression of CYCLIN B1;2 in a siamese mutant background caused a strongly enhanced phenotype.

Arabidopsis↗