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Cell Biology International (2005) 29, 10121018 (Printed in Great Britain)
Mitotic catastrophe and endomitosis in tumour cells: An evolutionary key to a molecular solution
Jekaterina Erenpreisaa*, M. Kalejsa and M.S. Craggbc
aLab. Tum. Cell Biol., Biomedicine Centre of the Latvia University, Ratsupites 1, Riga LV-1067, Latvia
bUniversity of Southampton, Southampton, UK
cWEHI, Melbourne, Australia
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.
Keywords: Mitotic catastrophe, Tumours, Endomitosis, Somatic reduction, Meiotic regulators.
*Corresponding author. Tel.: +371 7 808 220; fax: +371 7 442 407.
‘Treasure your exceptions’ (F. Schrader)
‘Treasure your exceptions’ (F. Schrader)
Following genotoxic insult, p53 mutated tumour cells undergo a process known as mitotic catastrophe (Hartwell and Kastan, 1994). This is characterised by a switch from mitosis (which is halted due to a profound arrest in metaphase) to the endocycle. Endocycles are also seen within normal tissues and are surprisingly common in the plant and animal kingdoms. Interestingly, the appearance of chromosomes during endocycles is highly varied. At one extreme they can appear fully polytenic as highly extended multinemic chromosomes, at the other extreme, during true endomitosis (as described by Geitler, 1937, 1939) they are displayed as multiple individual condensed chromosomes (or as diplochromosomes) within an intact nuclear envelope; partial polyteny, with some degree of multinemic chromosome compaction is also common (Nagl, 1990; Zybina and Zybina, 1996; Edgar and Orr-Weaver, 2001). Interestingly, all of these various forms of endocycle, including endomitosis, can also be observed in tumours (Levan and Haushka, 1953; Therman and Kuhn, 1989). In particular we and others have described the appearance of endopolyploid giant cells after genotoxic damage in tumours lacking wild type p53 function as a result of mitotic catastrophe (Illidge et al., 2000; Castedo et al., 2004).
Previously, mitotic catastrophe and endopolyploidy have been considered a reproductive dead-end. However, in recent years, we, and others, have provided data suggesting that this is not the case (Illidge et al., 2000; Erenpreisa et al., 2000; Erenpreisa and Cragg, 2001; Walen, 2002, 2004). Importantly, this data has now been confirmed in several independent laboratories with the use of direct video-imaging techniques studying the fate of individual cells, showing that after mitotic catastrophe a small proportion of endopolyploid tumour cells can survive, segregate successfully and return to mitosis (Prieur-Carrillo et al., 2003; Ianzini and Mackey, 2002, 2005; Sundaram et al., 2004; Mackey et al., 2003; Ianzini et al., 2002, 2005). These data indicate that tumour cells can, albeit with relatively low frequency, successfully switch from the endocycle back to mitosis. The question then arises as to how this is possible and which molecules regulate it? We have addressed this problem using insights gained from a knowledge of how endocycles are regulated throughout evolution and applied this to the tumour cell setting. Several aspects of these various endocycles will be discussed and may provide keys to how this problem is solved. First, we will discuss how and why the endocycle is initiated in tumour cells and how this parallels that seen in normal phylo- and onto-genesis.
2 Mitotic catastrophe and endomitosis occur not only in tumours, but in normal development
Mitotic catastrophe occurs in tumours following genotoxic insult or mitotic spindle damage and is apparently selected as an alternative to rapid apoptosis (Roninson et al., 2001). Subsequently, aberrant mitoses become aborted, restitute into interphase and the cells become endopolyploid. In this way, mostly 4C polyploid cells arise. However, higher levels of polyploidy, (at least up to 64C) are also observed and achieved through subsequent iterative endocycles. Importantly, a significant proportion of the endopolyploid cells (particularly from radioresistant cell-lines) appear to derive through endomitosis where condensed chromosomes are observed within intact nuclear envelope. These appear to initiate from either 4C, but more commonly, from 8C precursors, the latter developing from two aborted mitoses (personal observation on lymphoid tumours). Interestingly, exactly the same sequence of polyploidisation events and ploidy numbers have been described by researchers studying developmental polyploidy in various taxonomic forms (Nagl, 1978; Brodsky and Uryvaeva, 1985; Zybina and Zybina, 1996).
Anisimov and colleagues revealed a similar mechanism of reproduction in gland cells and neurons of the mollusc S. lauta (Anisimov and Kirsanova, 2002; Anisimov, 1997). The mechanism involves a switch from normal (complete) proliferative mitosis to an abnormal (incomplete) restitutional mitosis, followed by classical endomitosis (Geitler, 1937, 1939, 1953). As initially described by Geitler (1937), during classical endomitosis chromosomes are duplicated (endoreplicate), and proceed through condensation and de-condensation phases as endoprophase, endometaphase, endo-anaphase and endo-telophase whilst remaining static, without spindle formation or dissolution of the nuclear envelope.
The appearance of aberrant mitoses, (arrested in metaphase or more rarely in anaphase) or unequal segregation of chromosomal material leading to polyploidisation and endomitosis has also been observed during development. In fact, Geitler (1939) himself first noticed it in development of Water-hopper. Likewise, Anisimov (1997) described a strikingly high proportion of aberrant mitoses, up to 60%, during polyploidisation processes in the mollusc S. lauta. Similarly, up to 70% of a-cytokinetic mitoses were found at the stage of polyploidisation in the liver of newborn rats (Kudryavtsev, 1991, PhD theses in Russ., cited from Anisimov, 1997), and up to 80% of atypical metaphases at the polyploidisation stage in the mink trophoblast (Zybina et al., 1994). Presence of not only aberrant polyploidising mitoses but also cell death from arrested metaphases was also found during the normal development of the bone growth plate of embryonic chicken. Here the striking similarity to mitotic catastrophe in tumours after genotoxic damage was noted (Erenpreisa and Roach, 1999). Anisimov (1997, 1999, 2005) highlighted the sequence of aborted polyploidising mitosis and classic endomitosis as mutually compatible mechanisms of cell endopolyploidy. Clearly then, aberrant mitoses, endopolyploidy and endomitosis are reasonably commonplace and occur throughout evolution. Next we must consider how somatic reduction might occur.
3 Endomitosis is possibly linked to the evolution of meiosis
Somatic reduction of polyploidy in higher organisms is quite rare and most polyploid cells terminally differentiate and degenerate. However, somatic reduction can indeed be achieved in higher organisms and numerous examples are apparent (see reviews of Huskins, 1944 and Nagl, 1978). For example, in the mammalian trophoblast whole genomes segregate in the giant nucleus before death of these cells (Nagl, 1978; Zybina and Zybina, 1996, 2005). Furthermore, a small number of reduction divisions of octaploid cells are known to occur in the fox placenta (Zybina et al., 2001). However, although clearly possible, it should be noted that somatic reduction in higher organisms is still poorly understood (Edgar and Orr-Weaver, 2001; Storchova and Pellman, 2004). For this reason we have analysed the polyploid reduction processes that occur in lower organisms, such as protozoa. Some protozoans involve cycling polyploidy in their life-cycles, alternating between polyploidisation and de-polyploidisation phases (Raikov, 1982), making study of their genome reduction processes more straightforward. Furthermore, it is intriguing to note that certain aspects of the tumour cell response to genotoxic insult, involving polyploidy, depolyploidisation and segregation of genomes is reminiscent of the events of the asexual life-cycle of these protozoans (Erenpreisa et al., 2000).
In most protozoans, a fully-fledged sexual process (involving meiosis and syngamy) exists (Raikov, 1995), however, in some, the sexual life-cycle is not permanent and occasionally they revert to a more primitive process involving polyploidy/depolyploidy cycles. The interaction between these processes in the usually haploid flagellate Barbulanympha and other protozoans led Cleveland (1947) to suggest that this process formed the basis for the evolution of meiosis from mitosis. This idea is illustrated by the scheme presented in Fig. 1. As reported by Cleveland, polyploidy in Barbulanympha is invariably reduced by meiosis, and no degeneration results. The important part of this asexual life-cycle is that it is a two-step (somatic) meiosis where ‘chromosomes are synapsed and go to poles as dyads, in the first division, and as singles, in the second’ and where ‘meiosis is neither preceded nor followed by any kind of syngamy’ (Cleveland, 1947). A notable observation of Cleveland was that this meiosis is preceded by a monopolar endomitosis (Fig. 2, step 3). In fact, Cleveland even included endomitosis as the first step in meiosis. Endomitosis also precedes the somatic reduction and segregation of the primary polyploid nucleus of the radiolarian Aulocantha into isospores (not gametic cells) as reported by Grell (1953). In fact, both Cleveland (1947) and Grell (1953) and later Grell and Ruthmann (1964) all described the classical features of endomitosis initially reported by Geitler (1937, 1939).
The original scheme of Cleveland (1947) kindly supplemented by Dr. H. Zacharias Langwendel; (firstname.lastname@example.org) with a DNA-replication phase (in red), as DNA replication was not yet known in 1947. It shows the steps of evolution of meiosis from mitosis. Step 3 is deduced from polyploid forms of Barbulanympha showing that endomitosis is a prerequisite of a-sexual meiosis (somatic reduction).
Features of endomitotic tumour cells induced post-mitotic catastrophe. Apparent are the condensed chromosomes and intact nuclear envelope (smooth nuclear outlines), along with high nuclear concentration of cyclin B1 (FITC) counterstained with Propidium iodide (red), shown as panels (a) and (b) on the same cells. Panel (c) shows the distribution of telomeres detected by FISH; Panel (d) shows kinetochore staining (using immunofluoresce with the CREST-antibody (FITC), with DNA counterstained with DAPI (blue) and Beta-actin stained with falloidin-Texas red (red); Panel (e) demonstrates the formation of several metaphase/anaphase plates directly from endomitosis (DNA staining by the Feulgen-type reaction). Panels a)–d) are of Namalwa cells 5–8
In his 1953 publication, which included investigation of more than 4000 Aulocantha specimens, Grell concluded that endomitosis was undertaken in preparation for the subsequent reduction divisions of the polyploid nucleus. Endomitosis was observed in 9.1% of samples, yet somatic reduction was present in only 2.6%. So, like in tumours, it is clear that this is not a frequent and therefore easily observable process. In subsequent work, Grell and Ruthmann (1964) went on to demonstrate that axial structures were present between chromatids in the endomitotic chromosomes. After much dispute, these axial structures in the endomitotic chromosomes were agreed to represent the evolutionary predecessors of the meiotic synaptonemal complex. It was subsequently agreed that during endomitosis pairing of somatic bivalents probably occurs (Cachon et al., 1973). For this reason, endomitosis has been coined ‘meiosis without karyogamy’ (discussion rev. by Raikov, 1982). Interestingly, chromosomal pairing with true synaptonematic complexes is observed during the somatic reduction of the Pyrsonympha flagellate (Hollande and Carruette-Valentin, 1970). Unfortunately over time, with rare exceptions (Becak et al., 2003) knowledge of this work on endomitosis and its relationship to meiosis has been forgotten. Moreover, the existence of endomitosis as a specific kind of endocycle was for some time disputed (Therman et al., 1983; Brodsky and Uryvaeva, 1985; Anisimov, 1999) and molecular aspects of true endomitosis have not been well studied. Next, we shall consider what is currently known about the cytogenetic and molecular regulation of endomitosis.
4 Cytogenetic and molecular features of endomitosis
The accepted wisdom of how endocycles are regulated is based upon our knowledge of how mitosis is regulated. In short, endocycles are possible only when mitosis is suppressed. This occurs through down-regulation of the activity of the main driver of mitosis, the metaphase promoting complex (MPF) – which is composed of cyclin B and cdk1 (Grafi, 1998; Edgar and Orr-Weaver, 2001). Without this activity and the activity of the MPF-induced anaphase promoting complex, the cell is unable to compact, segregate, or move chromosomes.
Before continuing with this molecular analysis we must first note, as outlined earlier, there are important differences in the types of endocycles that cells undertake. In polytenic endocycles, DNA repeatedly duplicates but chromosomes remain uncoiled, probably due to the down-regulation of the mitotic molecular machinery (mostly cyclin B/Cdk1). In fact, even centromere and telomere heterochromatin sequences may be under-replicated due to an aborted late S-phase (Nagl, 1995; Lilly and Spradling, 1996; Edgar and Orr-Weaver, 2001). This is in contrast with the situation in endoreduplicating endomitotic cells where the genomes seem to be fully replicated (Zybina and Zybina, 1996). Furthermore, in endomitotic endocycles chromatin is condensed albeit to a variable extent which is a classical mitotic feature (Nagl, 1978, 1990). In fact, in tumour cell-lines high plasticity of endomitotic endochromosomes, from fully dispersed (Figs. 2a,b) to partially polytenic (Figs. 2c,d) is found, much as it was observed in tumours in vivo (Therman and Kuhn, 1989) and in polyploid protozoans (Raikov, 1982). The importance of chromosome condensation for de-polytenisation of partly interwoven multi-stranded chromosomes, and as a pre-requisite of genome segregation has been suggested by several authors (Grell, 1953; Nagl, 1978; Zybina and Zybina, 1996a, 2005; Bier, 1957).
Another difference between polytenic and endomitotic endocycles is that endomitotic tumour cells replicate telomeres (Fig. 2c) and centromeres (Fig. 2d) whilst truly polytenic tumour cells with extended decondensed chromatin do not (the latter also never segregate sub-cells, personal observations).
The truly endomitotic and partially polytenic endopolyploid tumour cells induced following gamma-irradiation express large amounts of nuclear cyclin B1 (Figs. 2a,b and 3a). This appears to be at least partly regulated by the MAPK pathway as the number of polyploid cells (particularly with ploidy over 8C) containing cyclin B1 is reduced by the addition of the MEK inhibitor UO126 (unpublished). Interestingly, endopolyploidy is also decreased by MEK inhibition in polyploid megakaryocytes (Rojnuckarin et al., 1999). The fact that the endomitotic endopolyploid tumour cells possess nuclear cyclin B1 and display chromosome condensation, indicates that the MPF is active in these cells. However, other known phosphorylating activities of the MPF such as mitotic spindle assembly and nuclear envelope disassembly, are not apparent. Clearly then, in endomitotic cells, MPF function is not typical and somehow partially abrogated. Abnormal cyclin B/cdk1 function during mitotic catastrophe was also noted by Castedo et al. (2004). Instead of progressing through mitosis, the endomitotic tumour cells which are mostly in endometaphase seem to activate the spindle checkpoint and thus prevent the degradation of cyclin B1. Presumably then, during the mitotic catastrophe and endomitosis of these endopolyploid tumour cells, another alternative non-mitotic signaling pathway must be in operation. It is intriguing therefore that an analogous requirement for these activities (spindle arrest and partial condensation of chromosomes) is also present during meiosis, where it is regulated by the MOS/MAPK pathway. During meiosis, mos is translationally up-regulated, where it stimulates the first division (reductional) of the cell and then further acts as a cytostatic factor to maintain the oocyte in metaphase arrest at meiosis II until fertilization occurs (Tachibana et al., 2000). These separate functions are attributed to two different downstream targets of the Mos/MAPK pathway, cdk1 and Rsk90, respectively (Phillips et al., 2002). In addition, Mos directly interacts with kinetochores thereby interrupting mitosis (Sagata, 1997).
Localisation of mos and cyclin B in endomitotic tumour cells post mitotic catastrophe. lmmunofluorescent detection of p39mos protein (FITC) and cyclin B (blue) with DNA counterstained with 7AAD (red). A partial co-localisation and co-ordinated regulation of both proteins is apparent, in accord with the extent of compaction/de-compaction of the partially polytenic endochromosomes: (a) endometaphase; (b) endotelophase. Images are of Namalwa cells irradiated 7
For this reason, we recently assessed the expression of Mos in our lymphoid tumour cells before and after irradiation. Intriguingly, we found that both by western blotting and immunostaining, Mos was significantly upregulated in p53-mutated but not wild type cells (paper submitted). These studies showed that partially polytenised endomitotic nuclei from endopolyploid cells contained large amounts of both Mos and cyclin B1, a proportion of which was colocalised (Fig. 3a). Furthermore, rare endotelophases from these cells showed co-operative down-regulation of both Mos and cyclin B1 coincident with de-condensation of the multinemic chromosomes (Fig. 3b).
In addition to Mos, we also discovered that other meiosis-specific genes were up-regulated in these tumour cells following mitotic catastrophe (Plakhins et al., 2005; Kalejs et al., submitted). Therefore, although not formally proven, it is likely that the appearance of mitotic catastrophe and endomitosis can be explained by the expression of important meiosis-specific regulators during aberrant mitosis. For example, in accord with its functions during meiosis, p39Mos could trigger the MEK/MAPK/Rsk90 pathway to switch off mitotic progression causing activation of the spindle checkpoint (Kosako et al., 1994; Tachibana et al., 2000) and allow polyploidisation in the absence of p53 function. In turn, down-regulation of the anaphase promoting complex signaled through the spindle checkpoint prevents degradation of cyclin B1, accounting for its nuclear accumulation and the condensation of the chromosomes, all of which are hallmarks of the sustained metaphase arrest caused by Mos (Maller et al., 2002). Furthermore, another function of the MPF, karyokinesis, is directly blocked by Mos through inactivation of kinetochores, and indirectly, through spindle checkpoint proteins. Within this scheme cyclical down-regulations of the Mos/MAPK cascade would allow S-phase and recombination to proceed. Recombination might be crucial both for reduction division (Petronczki et al., 2003) and also in surviving genotoxic damage. In support of this notion, we previously demonstrated DNA repair by homologous recombination in the endopolyploid tumour cells and provided evidence that this activity enhanced the survival of these cells (Ivanov et al., 2003).
Following recombination, it is currently unknown which molecular regulators are subsequently involved in the process leading to the segregation of the polyploid genome. However, it is clear that they do finally segregate nuclei which can assemble metaphase plates again (Fig. 2e) which then resume mitosis, as documented by us in an accompanying article (Erenpreisa et al., 2005).
The response of p53 non-functional tumour cells to genotoxic insult involves mitotic catastrophe and the induction of polyploidy. Although previously the induction of polyploidy was deemed a reproductive dead-end we, and others have indicated that this is not always the case. Through a series of defined complex nuclear rearrangements the endopolyploid tumour cells can successfully switch from the endocycle back to mitosis, through a process of somatic (genome) reduction.
In an attempt to discover the molecular regulators of the somatic reduction which occurs in these endopolyploid tumour cells, we took note of the fact that features reminiscent of mitotic catastrophe are also observed during normal development. This observation suggests that mitotic catastrophe is not simply a dysregulated deviation from the mitotic cycle caused by DNA damage but rather a programmed event. Indeed, both during ontogenetical development and in p53 mutated tumour cells, this response is linked to a specific form of the endocycle, endomitosis. Endomitosis was originally defined as ‘meiosis without karyogamy’ and is also observed in numerous phylogenetic and ontogenetic studies. Importantly, in the life cycles of several protozoa it is seen as a prerequisite of asexual meiosis enabling somatic reduction of polyploid nuclei. We therefore propose that endomitosis facilitates a similar function in endopolyploid tumour cells. Although current dogma suggests that the endocycle is simply a mitotic cycle with suppressed mitosis-engine machinery, the appearance of condensed chromosomes in the endomitotic cells does not fit with this paradigm. Instead it indicates that an additional molecular pathway is in operation. Again, in accordance with the evolutionary data mentioned above and recent experimental data in the tumour cell system, we suggest that key meiotic regulators, in particular, p39mos are involved in the induction of mitotic catastrophe and subsequent endomitosis. Furthermore, we suggest that meiotic regulators may also provide the molecular basis for somatic reduction and the return to mitosis of endopolyploid tumour cells.
Dr. Helmut Zacharias (Langwedel, Germany) is acknowledged for his help in the adaptation of the Cleveland scheme, both in its translation from old German-written articles and his interest in the problem. Thanks also to Dr. Harry Scherthan (BW Institute of Radiobiology, Munich, Germany) for his help in the telomere PNA FISH staining.
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