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Failure of cell cleavage induces senescence in tetraploid primary cells.

Panopoulos A, Pacios-Bras C, Choi J, Yenjerla M, Sussman MA, Fotedar R, Margolis RL - Mol. Biol. Cell (2014)

Bottom Line: Tetraploid primary cells quickly become quiescent, as determined by loss of the Ki-67 proliferation marker and of the fluorescent ubiquitination-based cell cycle indicator/late cell cycle marker geminin.Arrested tetraploid cells finally become senescent, as determined by SA-β-galactosidase activity.Tetraploid arrest is dependent on p16INK4a expression, as siRNA suppression of p16INK4a bypasses tetraploid arrest, permitting primary cells to become aneuploid.

View Article: PubMed Central - PubMed

Affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.

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Treatment with DCB does not arrest HCT116 p53+/+ cell proliferation. (A) HCT116 p53+/+ cells were treated with 10 μM DCB for 24 h and then released for the indicated times. The HCT116 cells proceed from tetraploidy to aneuploidy during 72 h of release. (B) HCT116 p53+/+ and HCT116 p53−/− were exposed to 10 μM DCB or 2 μg/ml Adriamycin (Skoufias et al., 2004) for 24 h and then released. Cell counts were then performed at the indicated times. Cells continue to proliferate when tetraploid and aneuploid, regardless of p53 status, but do not recover from Adriamycin.
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Figure 9: Treatment with DCB does not arrest HCT116 p53+/+ cell proliferation. (A) HCT116 p53+/+ cells were treated with 10 μM DCB for 24 h and then released for the indicated times. The HCT116 cells proceed from tetraploidy to aneuploidy during 72 h of release. (B) HCT116 p53+/+ and HCT116 p53−/− were exposed to 10 μM DCB or 2 μg/ml Adriamycin (Skoufias et al., 2004) for 24 h and then released. Cell counts were then performed at the indicated times. Cells continue to proliferate when tetraploid and aneuploid, regardless of p53 status, but do not recover from Adriamycin.

Mentions: To demonstrate a dual requirement for p53 and p16INK4a in the induction of senescence by tetraploidy, we assayed p53-competent HCT116 colon carcinoma cells. We found that HCT116 did not arrest when made tetraploid but continued first to 8N and then to aneuploidy (Figure 9A). In fact, p53+/+ HCT116 colon carcinoma cells continued to proliferate at the same pace as p53−/− HCT116 (Figure 9B). In contrast, exposure of the same cells to the DNA damage agent Adriamycin effectively blocked proliferation. Of importance, although HCT116 cells express wild-type p53, they do not express p16INK4a (Myohanen et al., 1998). These results indicate that expression of intact p53 is not sufficient to induce arrest in tetraploid cells.


Failure of cell cleavage induces senescence in tetraploid primary cells.

Panopoulos A, Pacios-Bras C, Choi J, Yenjerla M, Sussman MA, Fotedar R, Margolis RL - Mol. Biol. Cell (2014)

Treatment with DCB does not arrest HCT116 p53+/+ cell proliferation. (A) HCT116 p53+/+ cells were treated with 10 μM DCB for 24 h and then released for the indicated times. The HCT116 cells proceed from tetraploidy to aneuploidy during 72 h of release. (B) HCT116 p53+/+ and HCT116 p53−/− were exposed to 10 μM DCB or 2 μg/ml Adriamycin (Skoufias et al., 2004) for 24 h and then released. Cell counts were then performed at the indicated times. Cells continue to proliferate when tetraploid and aneuploid, regardless of p53 status, but do not recover from Adriamycin.
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Related In: Results  -  Collection

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Figure 9: Treatment with DCB does not arrest HCT116 p53+/+ cell proliferation. (A) HCT116 p53+/+ cells were treated with 10 μM DCB for 24 h and then released for the indicated times. The HCT116 cells proceed from tetraploidy to aneuploidy during 72 h of release. (B) HCT116 p53+/+ and HCT116 p53−/− were exposed to 10 μM DCB or 2 μg/ml Adriamycin (Skoufias et al., 2004) for 24 h and then released. Cell counts were then performed at the indicated times. Cells continue to proliferate when tetraploid and aneuploid, regardless of p53 status, but do not recover from Adriamycin.
Mentions: To demonstrate a dual requirement for p53 and p16INK4a in the induction of senescence by tetraploidy, we assayed p53-competent HCT116 colon carcinoma cells. We found that HCT116 did not arrest when made tetraploid but continued first to 8N and then to aneuploidy (Figure 9A). In fact, p53+/+ HCT116 colon carcinoma cells continued to proliferate at the same pace as p53−/− HCT116 (Figure 9B). In contrast, exposure of the same cells to the DNA damage agent Adriamycin effectively blocked proliferation. Of importance, although HCT116 cells express wild-type p53, they do not express p16INK4a (Myohanen et al., 1998). These results indicate that expression of intact p53 is not sufficient to induce arrest in tetraploid cells.

Bottom Line: Tetraploid primary cells quickly become quiescent, as determined by loss of the Ki-67 proliferation marker and of the fluorescent ubiquitination-based cell cycle indicator/late cell cycle marker geminin.Arrested tetraploid cells finally become senescent, as determined by SA-β-galactosidase activity.Tetraploid arrest is dependent on p16INK4a expression, as siRNA suppression of p16INK4a bypasses tetraploid arrest, permitting primary cells to become aneuploid.

View Article: PubMed Central - PubMed

Affiliation: Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.

Show MeSH
Related in: MedlinePlus