Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression

Bates, Stewart; Ryan, Kevin M.; Phillips, Andrew C.; Vousden, Karen H.

doi:10.1038/sj.onc.1202104

Cited by 174 publications

(168 citation statements)

References 42 publications

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“…In addition to enhancement of p53-independent apoptosis, cyclin G may contribute to p53-dependent apoptosis. It is clearly established that p53 can trans-activate cyclin G in a wide variety of cell lines (Bates et al, 1996;Okamoto and Beach, 1994;Zauberman et al, 1995;Okamoto et al, data not shown). It is thus possible that cyclin G co-operates with other p53 target genes to increase the extent of apoptosis after the activation of p53.…”

Section: Discussionmentioning

confidence: 94%

A role of cyclin G in the process of apoptosis

1999

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Cyclin G was previously identi®ed as a target gene of the p53 tumor suppresser protein, and levels of cyclin G are increased after induction of p53 by DNA damage. However, the function of cyclin G has not been established. To determine the e ect of increased expression of cyclin G, retroviruses encoding cyclin G were constructed and used to infect three di erent murine cell lines. Cyclin G protein levels induced by the retroviruses were within the range seen after DNA damage induction of p53. In each case we observed that such over-expression of cyclin G augments the apoptotic process. TNF-a induction of apoptosis is increased by expression of cyclin G in NIH3T3 ®broblasts which express p53, as well as in 10.1 ®broblasts which contain no p53 allele. Additionally, we observed that while cyclin G expression is markedly reduced upon aggregate formation in embryonic carcinoma P19 cells, retrovirus-mediated over-expression of cyclin G enhances apoptotic cell death in aggregated P19 cells, and increases the extent of apoptosis caused by retinoic acid or serum starvation of these cells. These data demonstrate that cyclin G plays a facilitating role in modulating apoptosis induced by di erent stimuli. Moreover, we have discovered that cyclin G expression is rapidly induced in P19 cells after exposure to Bone Morphogenic Protein-4 (BMP-4), suggesting that cyclin G may mediate apoptotic signals generated by BMP-4.

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Section: Discussionmentioning

confidence: 94%

A role of cyclin G in the process of apoptosis

1999

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“…Interestingly p21 Waf-1 is activated by microtubule damage and is required for microtubule damage checkpoint in mitosis and G1 phase of the cell cycle, helping to maintain genetic stability (Mantel et al, 1999;Niculescu et al, 1998). Despite e cient inhibition of cyclin E, A and B1 dependent kinase activity, cells released from an S phase block are not delayed in their ability to progress through S phase by the presence of p21 Waf-1 , Signi®cant numbers of cells released from the p21 Waf-1 activated G2 block, undergo endoreduplication passing through another S phase before mitosis (Bates et al, 1998). In other models, cells expressing high levels of p21 Waf-1 apparently progressed normally through S phase and enter in mitosis (Medema et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

SIAH-1 inhibits cell growth by altering the mitotic process

et al. 1999

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SIAH-1, the human homologue of the drosophila seven in absentia gene, is a p53-p21 Waf-1 inducible gene. We report that stable transfection with SIAH-1 of the epithelial breast cancer cell line MCF-7 blocks its growth process. The transfectants show a redistribution of SIAH-1 protein within the nucleus, more speci®cally to the nuclear matrix, associated to dramatic changes in cell morphology and defective mitosis. Multinucleated giant cells (2 ± 12 nuclei in more than 50% cells) were a most striking observation associated with tubulin spindle disorganization and defective cytokinesis. There were also present at high frequency abortive mitotic ®gures, DNA bridges and persistance of intercellular bridges and midbodies, along with an increased expression of p21 Waf-1 . These results indicate that the mechanism of growth arrest induced by SIAH-1 in MCF-7 cells involves disorganization of the mitotic program, mainly during nuclei separation and cytokinesis.

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“…To examine this possibility, we synchronized UTA-L1 cells by 48 h exposure to a serum-poor medium (0.5% FCS) followed by 20 h exposure to a serum-rich medium (10% FCS) in presence of 2 mM hydroxyurea. Under these conditions, the UTA-L1 cells tend to accumulate at the G1/S boundary ( Figure 7; Bates et al, 1998) and were then released (time`0' ) in a hydoxyurea-free serum-rich medium. Note that tetracycline was withdrawn from the medium of the induced cells at the time of plating in serum-poor medium, so that the timè 0' corresponds to about 3 days with regard to BCL6fg induction in`tet7' UTA-L1 cells (Figure 7a).…”

Section: Bcl6fg Expression Leads To An Ine Cient Progression In S Phasementioning

confidence: 99%

“…10 000 events were analysed for each sample. To synchronized U2OS derived clones, the cells were plated at high density in a serum poor medium (0.5% FCS) for 48 h, then refed with a serum rich medium (10% FCS) for 20 h in presence of hydroxyurea (2 mM) to block them at the G1/S boundary (Bates et al, 1998).…”

Section: Cell Cycle Analysismentioning

confidence: 99%

Overexpressed BCL6 (LAZ3) oncoprotein triggers apoptosis, delays S phase progression and associates with replication foci

et al. 1999

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One of the most frequent genetic abnormalities associated with non Hodgkin lymphoma is the structural alteration of the 5' non coding/regulatory region of the BCL6 (LAZ3) protooncogene. BCL6 encodes a POZ/ Zn ®nger protein, a structure similar to that of many Drosophila developmental regulators and to another protein involved in a human hematopoietic malignancy, PLZF. BCL6 is a sequence speci®c transcriptional repressor controlling germinal center formation and T cell dependent immune response. Although the expression of BCL6 negatively correlates with cellular proliferation in di erent cell types, the in¯uence of BCL6 on cell growth and survival is currently unknown so that the way its deregulation may contribute to cancer remains elusive. To directly address this issue, we used a tetracycline-regulated system in human U2OS osteosarcoma cells and thus found that BCL6 mediates growth suppression associated with impaired S phase progression and apoptosis. Interestingly, overexpressed BCL6 can colocalize with sites of ongoing DNA synthesis, suggesting that it may directly interfere with S phase initiation and/or progression. In contrast, the isolated Zn ®nger region of BCL6, which binds BCL6 target sequence but lacks transcriptional repression activity, slows, but does not suppress, U2OS cell growth, is less e cient at delaying S phase progression, and does not trigger apoptosis. Thus, for a large part, the e ects of BCL6 overexpression on cell growth and survival depend on its ability to engage protein/protein interactions with itself and/or its transcriptional corepressors. That BCL6 restricts cell growth suggests that its deregulation upon structural alterations may alleviate negative controls on the cell cycle and cell survival.

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Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression

Cited by 174 publications

References 42 publications

A role of cyclin G in the process of apoptosis

A role of cyclin G in the process of apoptosis

SIAH-1 inhibits cell growth by altering the mitotic process

Overexpressed BCL6 (LAZ3) oncoprotein triggers apoptosis, delays S phase progression and associates with replication foci

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