Differences in Mitotic Control among Mammalian Cells

Schimke, Robert T.; Kung, Andrew L.; Rush, Daphne F.; Sherwood, Sylvia

doi:10.1101/sqb.1991.056.01.049

Cited by 51 publications

(27 citation statements)

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“…Human diploid cells expressing T antigen displayed a compromised mitotic spindle checkpoint, a defect related to the spindle poison-induced polyploidy in some, but not all, human tumor cell lines (Kung et al, 1990;Roberts et al, 1990;Schimke et al, 1991;Lopes et al, 1993;Liebmann et al, 1994). Although Cross et al (1995) found that ®broblasts from p53 7/7 mouse embryos exhibited a defective mitotic spindle checkpoint, we have observed that osteosarcoma cell lines expressing p53 (U2OS) and lacking p53 (SaOS-2) are both susceptible to DNA rereplication in the presence of 100 ng/ml nocodazole (unpublished data), indicating that p53 status is not the sole determinant of spindle checkpoint integrity in transformed human cells.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, ®broblasts from wild type p53-expressing mice respect this spindle checkpoint, as assayed by¯ow cytometry, and refrain from undergoing a new round of DNA replication in the presence of an unassembled mitotic spindle. In a number of human cell lines, however, there was no obvious role for p53 in coupling the onset of DNA replication to the proper completion of mitosis (Kung et al, 1990;Roberts et al, 1990;Schimke et al, 1991;Lopes et al, 1993;Liebmann et al, 1994;Cross et al, 1995). Since transformed human cells were used in the above studies, we wanted to determine whether acute expression of T antigen, which binds to and inactivates wild type p53 (Lane and Crawford, 1979;Linzer and Levine, 1979;Oren et al, 1981) …”

Section: T Antigen Disrupts Three Mitotic Checkpoints Critical For Mamentioning

confidence: 99%

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Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Chang

Ray

et al. 1997

Oncogene

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SV40 large T antigen (T) inactivates the tumor suppressor proteins p53 and pRb, and can induce cells to enter DNA replication at inappropriate times. We show here that T also compromises three cell cycle checkpoints that regulate the entry into and exit from mitosis. Human diploid ®broblasts infected with a retrovirus expressing T displayed an attenuated radiation-induced mitotic delay, were more susceptible to chemical-induced uncoupling of mitosis from the completion of DNA replication, and were more likely to exit mitosis and rereplicate their DNA when mitotic spindle assembly was inhibited. Consistent with altered mitotic checkpoint control, cells expressing T displayed elevated protein levels and/or associated activities of the mitotic regulatory proteins cyclin A, cyclin B, Cdc25C and p34 cdc2 . These changes in mitotic control were evident within 5 ± 10 population doublings after retroviral infection, indicating a direct e ect of T expression. Cells acutely infected with the T-expressing retrovirus su ered numerical and structural chromosome aberrations, including increases in aneuploidy, dicentric chromosomes, chromatid exchanges and chromosome breaks and gaps. These ®ndings indicate that T rapidly disrupts mitotic checkpoints that help maintain genomic stability, and suggest mechanisms by which T induces chromosome aberrations and promotes the immortalization and neoplastic transformation of human cells.

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Section: Discussionmentioning

confidence: 99%

Section: T Antigen Disrupts Three Mitotic Checkpoints Critical For Mamentioning

confidence: 99%

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Chang

Ray

et al. 1997

Oncogene

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“…Rodent cells have a relaxed checkpoint response to nocodazole More than 10 years ago, Schimke et al (1991) (Kung et al, 1990) reported that human and rodent cells behaved differently when exposed to microtubule interfering agents. When treated with such drugs, human cells halted mitosis while rodent cells continued to progress and exited mitosis.…”

Section: Resultsmentioning

confidence: 99%

“…Using microtubule depolymerizing drugs, they noted that in response to mitotic spindle disruption, human cells arrested cell cycle progression in metaphase while rodent cells continued to progress, leading to multiplication of DNA content (Kung et al, 1990;Schimke et al, 1991). Such an apparently relaxed mitotic checkpoint may contribute to genomic instability which could subsequently lead to neoplastic transformation (Schimke et al, 1991;Hartwell, 1992;Murray, 1992;Lengauer et al, 1997;Duesberg and Li, 2003).…”

Section: à10mentioning

confidence: 99%

The N-terminus of rodent and human MAD1 confers species-specific stringency to spindle assembly checkpoint

et al. 2005

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The spindle assembly checkpoint (SAC) guards against chromosomal mis-segregation and the emergence of aneuploidy. SAC in higher eukaryotes includes at least 10 proteins including MAD1-3, BUB1-3, and Msp1. A long-standing observation has been that rodent cells are more tolerant of microtubule toxins than primate cells indicating that SAC function is more relaxed in the former than the latter. Here, we report on an unexpected functional difference between the rodent and human MAD1 component of the respective SAC. Ectopic expression of human MAD1 in mouse and hamster cells corrected a relaxed SAC to a more stringent form. Our findings posit MAD1 as a species-specific determinant which influences the stringency of cellular response to microtubule depolymerization and spindle damage.

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“…This mechanism can logically be expected to ensure the assembly of a functioning mitotic spindle before exit from mitosis. But in actuality, cells have a widely varied capacity to arrest in mitosis in the presence of microtubule inhibitors (Kung et al, 1990;Schimke et al, 1991;Cahill et al, 1998), and many nontransformed cells undergo only a transient mitotic arrest, and then exit mitosis without chromosome segregation and become tetraploid (Minn et al, 1996;Lanni and Jacks, 1998). However, a p53-dependent backup mechanism induces G1 arrest in cells that have evaded mitotic arrest imposed by inhibitors of microtubule assembly (Minn et al, 1996;Lanni and Jacks, 1998).…”

Section: Introductionmentioning

confidence: 99%

Tetraploid State Induces p53-dependent Arrest of Nontransformed Mammalian Cells in G1

Andreassen

Lohez

Lacroix

et al. 2001

MBoC

389

412

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A "spindle assembly" checkpoint has been described that arrests cells in G1 following inappropriate exit from mitosis in the presence of microtubule inhibitors. We have here addressed the question of whether the resulting tetraploid state itself, rather than failure of spindle function or induction of spindle damage, acts as a checkpoint to arrest cells in G1. Dihydrocytochalasin B induces cleavage failure in cells where spindle function and chromatid segregation are both normal. Notably, we show here that nontransformed REF-52 cells arrest indefinitely in tetraploid G1 following cleavage failure. The spindle assembly checkpoint and the tetraploidization checkpoint that we describe here are likely to be equivalent. Both involve arrest in G1 with inactive cdk2 kinase, hypophosphorylated retinoblastoma protein, and elevated levels of p21 WAF1 and cyclin E. Furthermore, both require p53. We show that failure to arrest in G1 following tetraploidization rapidly results in aneuploidy. Similar tetraploid G1 arrest results have been obtained with mouse NIH3T3 and human IMR-90 cells. Thus, we propose that a general checkpoint control acts in G1 to recognize tetraploid cells and induce their arrest and thereby prevents the propagation of errors of late mitosis and the generation of aneuploidy. As such, the tetraploidy checkpoint may be a critical activity of p53 in its role of ensuring genomic integrity. INTRODUCTIONAneuploidy is common among tumor cells and frequently follows after an intermediate tetraploid state (Shackney et al., 1989;Galipeau et al., 1996). The presence of aneuploidy in tumors is correlated with metastatic progression and poor prognosis (Sandberg, 1977;Rabinovitch et al., 1989). A carefully studied progression toward tumor status in Barrett's esophagus cells has shown that the precancerous state is characterized by loss of p53 function, followed by tetraploidy, and then aneuploidy (Galipeau et al., 1996). Subversion of the capacity of the cell to evade the consequences of tetraploidization, which inevitably leads to aneuploidy, may be a common intermediate in the multistep process by which tumor cells arise in situ.Tetraploidy can arise by exit of a cell from mitosis following failures of spindle assembly, of chromosome segregation, or of cytokinesis . Mammalian cells have a checkpoint that maintains cdc2-cyclin B activity and induces mitotic arrest in the presence of inhibitors of microtubule assembly (Kung et al., 1990;Andreassen and Margolis, 1994). This mechanism can logically be expected to ensure the assembly of a functioning mitotic spindle before exit from mitosis. But in actuality, cells have a widely varied capacity to arrest in mitosis in the presence of microtubule inhibitors (Kung et al., 1990;Schimke et al., 1991;Cahill et al., 1998), and many nontransformed cells undergo only a transient mitotic arrest, and then exit mitosis without chromosome segregation and become tetraploid (Minn et al., 1996;Lanni and Jacks, 1998). However, a p53-dependent backup mechanism induces G1 arrest in cell...

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Differences in Mitotic Control among Mammalian Cells

Cited by 51 publications

References 0 publications

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

Disregulation of mitotic checkpoints and regulatory proteins following acute expression of SV40 large T antigen in diploid human cells

The N-terminus of rodent and human MAD1 confers species-specific stringency to spindle assembly checkpoint

Tetraploid State Induces p53-dependent Arrest of Nontransformed Mammalian Cells in G1

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