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PubMed1999

X-irradiation of G1 CHO cells induces SCE which are both true and false in BrdU-substituted cells but only false in biotin-dUTP-substituted cells.

The SCE-test is widely used in genetic toxicology and therefore knowledge of the contribution of BrdU to the formation of spontaneous and induced SCE is of great importance. The present study was undertaken to analyse the role of BrdU in X-ray-induced SCE. If SCE resulted from inversions, rings and double minutes (RDM) would be the asymmetrical counterparts of SCE and should therefore have the same frequencies. Dose-effect relationships of SCE and RDM show that the frequencies of SCE are much higher than those of RDM. We conclude that only a few SCE may represent inversions. In a second set of experiments, endoreduplications were induced in cells irradiated either before or after labelling with BrdU. Analysis of SCE in endoreduplicated chromosomes allows the discrimination of the cell cycle in which they originated. The results show that SCE are only induced in the first cell cycle following irradiation of BrdU-substituted cells, indicating that labelling with BrdU is a necessary prerequisite for the formation of SCE. In order to test this directly, radiation-induced SCE frequencies were studied in cells prelabelled with BrdU or biotin-dUTP in a third set of experiments. The structure of biotin-dUTP suggests that, in contrast to BrdU, it does not give rise to radicals during irradiation. Significantly lower frequencies of SCE were observed in biotin-dUTP-substituted cells than in BrdU-labelled cells. Calculations show that nearly all SCE induced in biotin-dUTP-labelled chromosomes can be explained by chromosomal aberrations (false SCE). In contrast to this, most SCE induced by X-rays in BrdU-labelled cells are not due to chromosomal aberrations, but result from S-dependent lesions (true SCE). This clearly points towards radiation damage in BrdU-moieties as the source of DNA lesions leading to SCE.

Animals↗
PubMed1999

P53-dependent effects of RAS oncogene on chromosome stability and cell cycle checkpoints.

Mutations activating the function of ras proto-oncogenes are often observed in human tumors. Their oncogenic potential is mainly due to permanent stimulation of cellular proliferation and dramatic changes in morphogenic reactions of the cell. To learn more on the role of ras activation in cancerogenesis we studied its effects on chromosome stability and cell cycle checkpoints. Since the ability of ras oncogenes to cause cell transformation may be dependent on activity of the p53 tumor-suppressor the cells with different p53 state were analysed. Ectopic expression of N-ras(asp12) caused in p53-deficient MDAH041 cell line an augmentation in the number of chromosome breaks in mitogenic cells, significant increase in the frequency of metaphases showing chromosome endoreduplication and accumulation of polyploid cells. Similar effects were induced by different exogenous ras genes (N-ras(asp12), H-ras(leu12), N-ras proto-oncogene) in Rat1 and Rat2 cells which have a defect in p53-upstream pathways. In contrast, in REF52 and human LIM1215 cells showing ras-induced p53 up-regulation, ras expression caused only slight increase in the number of chromosome breaks and did not enhance the frequency of endoreduplication and polyploidy. Inactivation in these cells of p53 function by transduction of dominant-negative C-terminal p53 fragment (genetic suppressor element #22, GSE22) or mutant p53s significantly increased the frequency of both spontaneous and ras-induced karyotypic changes. In concordance with these observations we have found that expression of ras oncogene caused in p53-defective cells further mitigation of ethyl-metansulphonate-induced G1 and G2 cell cycle arrest, but did not abrogate G1 and G2 cell cycle checkpoints in cells with normal p53 function. These data indicate that along with stimulation of cell proliferation and morphological transformation ras activation can contribute to cancerogenesis by increasing genetic instability.

Animals↗
PubMed1999

Cytokine response gene 6 induces p21 and regulates both cell growth and arrest.

Cytokine response gene #6 (CR6), cloned from interleukin 2-stimulated T lymphocytes, is homologous to GADD45 and MyD118, genes which promote cell cycle arrest and apoptosis. To determine how this gene family could possibly mediate both cell survival/proliferation and cell cycle arrest/death, transfectants were generated so that the genes could be expressed ectopically, independently from their normal inducing agents. In cycling retinoblastoma protein-negative (pRb-) cells, ectopic CR6 expression blocked G2/M transition, but did not prevent G1/S transition so that endoreduplication resulted. By comparison, when CR6, GADD45, and MyD118 genes were expressed ectopically in proliferating pRb+ cells, either G1/S or G2/M transition was effectively blocked, so that there was no endoreduplication. Consistent with these findings, in proliferating pRb-cells, ectopic expression of CR6 promoted the expression of both G1 and G2/M cyclins. By comparison, in pRb+ cells, the expression of G1 cyclins was increased, while expression of the mitotic cyclins was decreased. However, in pRb+ cells, cyclin-dependent kinase activities associated with both G1 and G2/M cyclins were decreased. Moreover, ectopic expression of all three genes resulted in the expression of the CKI, p21, both in pRb- and pRb+ cells. The physiologic induction of CR6 expression by IL2 in quiescent normal human T cells occurs transiently in the first half of G1, coordinately with the expression of p21. Therefore, this gene family regulates G1 and G2, and promotes either cell growth or arrest by a common mechanism.

Carrier Proteins↗
PubMed1998

Near-haploid common acute lymphoblastic leukaemia of childhood with a second hyperdiploid line: a DNA ploidy and fluorescence in-situ hybridization study.

Near-haploidy is a rare cytogenetic finding in childhood acute lymphoblastic leukaemia (ALL) and is associated with a poor prognosis. A second hyperdiploid line, occurring presumably by endoreduplication of the near-haploid stemline, is often observed. We present a case of common ALL in relapse characterized morphologically by a dual population of small and large lymphoblasts. Cytogenetic analysis supplemented with fluorescence in-situ hybridization (FISH) studies localized near-haploidy and hyperdiploidy to the small and large blast population respectively. DNA ploidy determination confirmed two abnormal clones with near-haploidy as the predominant one. A novel t(9;12)(q11;q13) was present in the near-haploid clone and was duplicated in the hyperdiploid clone. This finding identified cells bearing near-haploidy to be the clonogenic population following malignant transformation and confirmed endoreduplication as the mechanism for the presence of associated hyperdiploidy.

Child↗
PubMed1996

Induction of cdc2a and cyc1At expression in Arabidopsis thaliana during early phases of nematode-induced feeding cell formation.

Root-knot and cyst nematodes are plant parasites that induce large multinucleated feeding cells in the roots of their hosts. Cytological observations have shown that root-knot nematodes induce giant cells by cycles of mitosis without cytokinesis whereas cyst nematodes provoke cell wall degradation leading to the formation of a large syncytium. This study was intended to characterize and compare the ability of both types of nematodes to induce progression through the cell cycle. For this purpose, the expression, upon nematode infection, of two cell cycle markers was followed: a marker for division competence, the cyclin-dependent kinase cdc2a and a marker for the G2 phase, the mitotic cyclin cyc1At. For both types of nematodes, transcriptional activation of these markers was correlated with early phases of feeding cell development. Using molecular markers, it was thus possible to confirm and extend the observations of repeated mitosis in root-knot nematode-induced giant cells. Surprisingly, promoter activation of both cdc2a and cyc1At markers was also found upon cyst nematode infection, in feeding cells in which mitosis has not been clearly reported. Incorporation of tritiated thymidine in these syncytia confirms that they progress through the S phase of the cell cycle. One possibility is that cyst nematodes induce cycles of DNA endoreduplication shunting the M phase. Despite obvious differences in ontogeny, common molecular mechanisms, involving cycles of DNA endoreduplication and cdc2a and cyc1At expression, might thus be involved in the formation of a giant cell or a syncytium.

Animals↗
PubMed2001

A role for salicylic acid and NPR1 in regulating cell growth in Arabidopsis.

Salicylic acid (SA) plays a key role in activating defenses and cell death during plant-pathogen interactions. In response to some pathogens, SA also limits the extent of cell death, indicating that it acts positively or negatively depending on the host-pathogen interaction. In addition, we previously showed that SA affects cell growth in the Arabidopsis defense-related mutants accelerated cell death 6-1 (acd6-1) and aberrant growth and death 2 (agd2). Using acd6-1, agd2 and two other defense-related mutants, lesion simulating disease 6 (lsd6), suppressor of SA-insensitivity (ssi1), we show here in detail that SA regulates cell growth by specifically affecting cell enlargement, endoreduplication and/or cell division. We find that SA can act either positively or negatively to regulate cell growth depending on the context in which signaling occurs. Additionally, Nonexpressor of PR 1 (NPR1), a key SA signaling protein important for regulating defenses and cell death, also acts to promote cell division and/or suppress endoreduplication during leaf development. We propose that SA interacts with multiple receptors or signaling pathways to control cellular alterations during normal development, pathogen attack and/or stress situations. We suggest that SA and NPR1 play broader roles in cell fate control than has previously been understood.

Arabidopsis↗
PubMed2002

Cell cycle progression during endosperm development in Zea mays depends on parental dosage effects.

Interploidy crosses in flowering plants often cause seed abortion. Studies in maize have shown that failure of kernel development results from dosage effects among products of imprinted but as-yet-unknown genes in the endosperm, and that the operative stoichiometry is established for a ratio of two maternal genomes to one paternal genome. In this study, we used flow cytometry to monitor cell cycle activities in developing endosperms obtained after reciprocal crosses between diploid and tetraploid maize individuals. Our data show that dosage effects alter critical events involved in the establishment of endoreduplication during maize endosperm development. Particularly, maternal genomic excess (4x x 2x crosses) forces endosperm cells to enter early into endoreduplication while paternal genomic excess (2x x 4x crosses) prevents its establishment. Our results also suggest that altering mechanisms depend on two different sets of cell cycle regulatory genes--one imprinted through the female that is required for mitotic arrest, and another responsible for re-entry into S phase that is imprinted through the male. Further, molecular and physiological analyses should provide insights into the interaction of parental imprinting action and cell cycle regulation during endosperm development.

Cell Cycle↗
PubMed2006

Eukaryotic control on bacterial cell cycle and differentiation in the Rhizobium-legume symbiosis.

Symbiosis between legumes and Rhizobium bacteria leads to the formation of root nodules where bacteria in the infected plant cells are converted into nitrogen-fixing bacteroids. Nodules with a persistent meristem are indeterminate, whereas nodules without meristem are determinate. The symbiotic plant cells in both nodule types are polyploid because of several cycles of endoreduplication (genome replication without mitosis and cytokinesis) and grow consequently to extreme sizes. Here we demonstrate that differentiation of bacteroids in indeterminate nodules of Medicago and related legumes from the galegoid clade shows remarkable similarity to host cell differentiation. During bacteroid maturation, repeated DNA replication without cytokinesis results in extensive amplification of the entire bacterial genome and elongation of bacteria. This finding reveals a positive correlation in prokaryotes between DNA content and cell size, similar to that in eukaryotes. These polyploid bacteroids are metabolically functional but display increased membrane permeability and are nonviable, because they lose their ability to resume growth. In contrast, bacteroids in determinate nodules of the nongalegoid legumes lotus and bean are comparable to free-living bacteria in their genomic DNA content, cell size, and viability. Using recombinant Rhizobium strains nodulating both legume types, we show that bacteroid differentiation is controlled by the host plant. Plant factors present in nodules of galegoid legumes but absent from nodules of nongalegoid legumes block bacterial cell division and trigger endoreduplication cycles, thereby forcing the endosymbionts toward a terminally differentiated state. Hence, Medicago and related legumes have evolved a mechanism to dominate the symbiosis.

Cell Cycle↗
PubMed2002

Ectopic D-type cyclin expression induces not only DNA replication but also cell division in Arabidopsis trichomes.

Although the mechanisms controlling the two cell-cycle checkpoints G(1)-S and G(2)-M are well studied, it remains elusive how they are linked in higher eukaryotes. In animals, D-type cyclins have been implicated in the control of cell-cycle progression in mitotic as well as in endoreduplicating cells. By contrast, we show that the expression of the D-type cyclin CYCD3;1 in endoreduplicating Arabidopsis trichome cells not only induced DNA replication but also cell divisions.

Arabidopsis↗
PubMed2000

Somatic polyploidization and cellular proliferation drive body size evolution in nematodes.

Most of the hypodermis of a rhabditid nematode such as Caenorhabditis elegans is a single syncytium. The size of this syncytium (as measured by body size) has evolved repeatedly in the rhabditid nematodes. Two cellular mechanisms are important in the evolution of body size: changes in the numbers of cells that fuse with the syncytium, and the extent of its acellular growth. Thus nematodes differ from mammals and other invertebrates in which body size evolution is caused by changes in cell number alone. The evolution of acellular syncytial growth in nematodes is also associated with changes in the ploidy of hypodermal nuclei. These nuclei are polyploid as a consequence of iterative rounds of endoreduplication, and this endocycle has evolved repeatedly. The association between acellular growth and endoreduplication is also seen in C. elegans mutations that interrupt transforming growth factor-beta signaling and that result in dwarfism and deficiencies in hypodermal ploidy. The transforming growth factor-beta pathway is a candidate for being involved in nematode body size evolution.

Animals↗
PubMed2001

The NEDD8 system is essential for cell cycle progression and morphogenetic pathway in mice.

NEDD8/Rub1 is a ubiquitin (Ub)-like molecule that covalently ligates to target proteins through an enzymatic cascade analogous to ubiquitylation. This modifier is known to target all cullin (Cul) family proteins. The latter are essential components of Skp1/Cul-1/F-box protein (SCF)-like Ub ligase complexes, which play critical roles in Ub-mediated proteolysis. To determine the role of the NEDD8 system in mammals, we generated mice deficient in Uba3 gene that encodes a catalytic subunit of NEDD8-activating enzyme. Uba3(-/-) mice died in utero at the periimplantation stage. Mutant embryos showed selective apoptosis of the inner cell mass but not of trophoblastic cells. However, the mutant trophoblastic cells could not enter the S phase of the endoreduplication cycle. This cell cycle arrest was accompanied with aberrant expression of cyclin E and p57(Kip2). These results suggested that the NEDD8 system is essential for both mitotic and the endoreduplicative cell cycle progression. beta-Catenin, a mediator of the Wnt/wingless signaling pathway, which degrades continuously in the cytoplasm through SCF Ub ligase, was also accumulated in the Uba3(-/-) cytoplasm and nucleus. Thus, the NEDD8 system is essential for the regulation of protein degradation pathways involved in cell cycle progression and morphogenesis, possibly through the function of the Cul family proteins.

Animals↗
PubMed2003

Response of potato tuber cell division and growth to shade and elevated CO2.

Plants adjust their sink-organ growth rates, development and distribution of dry matter in response to whole-plant photosynthate status. To advance understanding of these processes, potato (Solanum tuberosum L.) plants were subjected to CO(2) and light flux treatments, and early tuber growth was assessed. Atmospheric CO(2) (700 or 350 micro mol mol(-1)) and light flux (shade and control illumination) treatments were imposed at two growth stages: tuber initiation (TI) and tuber bulking (TB). Elevated CO(2) increased accumulation of total net biomass when imposed at both stages, and increased tuber growth rate by about 36 %, but did not increase the number of tubers. Elevated CO(2) increased the number of cells in tubers at both TI and TB stages, whereas shade substantially decreased the number of cells at both stages. Generally, treatments did not affect cell volume or the proportion of nuclei endoreduplicating (repeated nuclear DNA replication in the absence of cell division), but the shade treatment led to a decrease in cell volume at TB and a decrease in endoreduplication at TI. Elevated CO(2) increased, and shade decreased, glucose concentration and soluble invertase activity in the cambial zones at both TI and TB, whereas sucrose concentration and activities of glucokinase, fructokinase, cell-wall-bound invertase and thymidine kinase were unaffected. Modulation of tuber cell division was responsible for much of the growth response to whole-plant photosynthate status, and treatments affected cambial-zone glucose and soluble invertase in a pattern suggesting involvement of a glucose signalling pathway.

Carbohydrate Metabolism↗
PubMed2004

Analysis of the spatial expression pattern of seven Kip related proteins (KRPs) in the shoot apex of Arabidopsis thaliana.

BACKGROUND AND AIMS: Kip-related-proteins (KRPs), negative regulators of cell division, have recently been discovered in plants but their in planta function is as yet unclear. In this study the spatial expression of all seven KRP genes in shoot apices of Arabidopsis thaliana were compared. METHODS: In situ hybridization analyses were performed on longitudinal sections of shoot apices from 2-month-old Arabidopsis plants. KEY RESULTS: The study provides evidence for different expression pattern groups. KRP1 and KRP2 expression is restricted to the endoreduplicating tissues. In contrast, KRP4 and KRP5 expression is mainly restricted to mitotically dividing cells. KRP3, KRP6 and KRP7 can be found in both mitotically dividing and endoreduplicating cells. CONCLUSION: The results suggest differential roles for the distinct KRPs. KRP1 and KRP2 might specifically be involved in the establishment of polyploidy. In contrast, KRP4 and KRP5 might be involved in regulating the progression through the mitotic cell cycle. KRP3, KRP6 and KRP7 might have a function in both types of cell cycle.

Arabidopsis↗
PubMed1999

Trichome cell growth in Arabidopsis thaliana can be derepressed by mutations in at least five genes.

Leaf trichomes in Arabidopsis are unicellular epidermal hairs with a branched morphology. They undergo successive endoreduplication rounds early during cell morphogenesis. Mutations affecting trichome nuclear DNA content, such as triptychon or glabra3, alter trichome branching. We isolated new mutants with supernumerary trichome branches, which fall into three unlinked complementation groups: KAKTUS and the novel loci, POLYCHOME and RASTAFARI. They map to chromosomes IV, II, and V, respectively. The trichomes of these mutants presented an increased DNA content, although to a variable extent. The spindly-5 mutant, which displays a constitutive gibberellin response, also produces overbranched trichomes containing more nuclear DNA. We analyzed genetic interactions using double mutants and propose that two independent pathways, defined by SPINDLY and TRIPTYCHON, act to limit trichome growth. KAKTUS and POLYCHOME might have redundant actions mediating gibberellin control via SPINDLY. The overall leaf polysomaty was not notably affected by these mutations, suggesting that they affect the control of DNA synthesis in a tissue- or cell type-specific manner. Wild-type tetraploids also produce overbranched trichomes; they displayed a shifted polysomaty in trichomes and in the whole leaf, suggesting a developmental program controlling DNA increases via the counting of endoreduplication rounds.

Alleles↗
PubMed2006

A human tetraploid pachytene spermatocyte as the possible origin of diploid sperm: a case report.

Diploid spermatozoa represent 0.2-0.3% of all spermatozoa in the normal population and cause 8.3% of diandric triploids. Errors in meiosis I and II are the most common mechanisms by which diploid spermatozoa are produced. Endoreduplication before meiosis has been suggested as a possible origin for tetraploid meiocytes, which might, in turn, produce diploid sperm. Synaptonemal complex (SC) spreads of a fertile man were immunolabelled (SCP3, MLH1 and CENP) and hybridized with subtelomere-specific multiplex fluorescent in situ hybridization (stM-FISH) assay for SCs identification. The unexpected finding of a tetraploid pachytene cell and the identification of all of its SCs demonstrate that synapsis and crossover events can occur in human tetraploid cells. Moreover, it indicates that diploid sperm may also originate from mitotic errors (endoreduplication) occurring before meiosis.

Aneuploidy↗
PubMed1998

Translational inhibition of cyclin B1 and appearance of cyclin D1 very early in the differentiation of mouse trophoblast giant cells.

Investigation of the basis of uncoupling of replication of the genome from mitosis in the mouse trophoblast has so far been neglected despite its significance for understanding both placental development and cell cycle control. In order to obtain clues about the molecular basis of the switch from proliferation to endoreduplication, we have investigated changes in the expression of cyclins and cyclin-dependent kinases in diploid versus giant trophoblast cells. Interestingly, while cyclin B1 transcripts were found in both diploid and giant cells, the protein was found exclusively in diploid cells. This could be explained by either inhibition of translation or by constitutive degradation of the protein. The latter was ruled out by examining blastocysts which had been cultured in the presence of the proteasome inhibitor N-acetyl-leu-leu-norleucinal followed by immunostaining for cyclin B1. In these experiments cyclin B1 protein accumulated in diploid but not in giant cells. Fusion of trophoblast giant cells with secondary oocytes, which are rich in maturation promoting factor (MPF) activity, revealed that an exogenous source of active MPF could cause chromosome condensation and nuclear envelope breakdown in endocycling cells; therefore endoreduplication via polyteny evidently requires the suppression of MPF activity. In addition, cyclin D1 transcripts were found only in giant cells and, interestingly, the beginning of its expression was evident prior to that of placental lactogen I, an early marker of trophoblast differentiation. The results suggest that supression of MPF activity, by inhibition of translation of cyclin B1, is a key mechanism for the establishment of the endocycle in the mouse trophoblast.

Animals↗
PubMed1991

Premature chromosome condensation as a sign of oocyte immaturity.

In this work we report the possibility that oocyte immaturity is associated with premature chromosome condensation (PCC) after in-vitro fertilization (IVF). Using a murine model, we have related PCC and endoreduplicated-like oocytes to oocyte immaturity as a basis for a prognosis in oocyte immaturity problems. The cytogenetic analysis was performed in 511 embryos obtained from immature oocytes that were directly fertilized in vitro and in 1363 embryos obtained from immature oocytes that were matured in vitro with different concentrations of human chorionic gonadotrophin (HCG) added to the culture medium. As a control we used 507 embryos obtained from freshly ovulated oocytes. PCC at the G1-phase-(G1-PCC) was observed only when immature oocytes were immediately fertilized in vitro (45.4%) and PCC at the S-phase (S-PCC) only when using in-vitro matured oocytes with the highest HCG concentration (3.3%). Neither G1-PCC nor S-PCC were found in the control group. Endoreduplicated-like oocytes appeared in a significant percentage (27.3%) only in the immature group. Immature oocytes yielded a low fertilization rate (16.6%) while in-vitro maturation seemed to confer a higher fertilization capacity compared to the control group (90.1% versus 78.2%). The possible correlation between PCC and oocyte immaturity provides new prospects in the determination of human IVF failures of unknown origin. Thus, when a problem of oocyte immaturity is diagnosed through the presence of PCC, a special programme of in vitro oocyte maturation, such as a longer preincubation time or addition of hormones to the media, would be recommended.

Aneuploidy↗
PubMed1998

Drosophila myb is required for the G2/M transition and maintenance of diploidy.

The myb proto-oncogenes are thought to have a role in the cell division cycle. We have examined this possibility by genetic analysis in Drosophila melanogaster, which possesses a single myb gene. We have described previously two temperature-sensitive, recessive lethal mutants in Drosophila myb (Dm myb). The phenotypes of these mutants revealed a requirement for myb in diverse cellular lineages throughout the course of Drosophila development. We now report a cellular explanation for these findings by showing that Dm myb is required for both mitosis and prevention of endoreduplication in wing cells. Myb apparently acts at or near the time of the G2/M transition. The two mutant alleles of Dm myb produce the same cellular phenotype, although the responsible mutations are located in different functional domains of the gene product. The mutant phenotype can be partially suppressed by ectopic expression of either cdc2 or string, two genes that are known to promote the transition from G2 to M. We conclude that Dm myb is required for completion of cell division and may serve two independent functions: promotion of mitosis, on the one hand, and prevention of endoreduplication when cells are arrested in G2, on the other.

Amino Acid Sequence↗