Characterization of p53 in Chinese hamster cell lines CHO-K1, CHO-WBL, and CHL: implications for genotoxicity testing

Hu, Ting; Miller, C. M.; Ridder, Gregg M.; Aardema, Marilyn J.

doi:10.1016/s0027-5107(99)00077-9

Cited by 102 publications

(61 citation statements)

References 29 publications

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“…It is important to note that CHO cells are mutated for p53 (Lee et al, 1997;Hu et al, 1999). In the cell line we were working with, p53 was not detectable and there was no transactivation of a p53-driven vector (data not shown).…”

Section: Discussionmentioning

confidence: 98%

Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation

Dunkern¹,

Fritz²,

Kaina³

2001

Oncogene

105

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Ultraviolet (UV) light is a potent mutagenic and genotoxic agent. Whereas DNA damage induced by UV light is known to be responsible for UV-induced genotoxicity, its role in triggering apoptosis is still unclear. We addressed this issue by comparing nucleotide excision repair (NER) de®cient 27-1 and 43-3B Chinese hamster (CHO) cells with the corresponding wild-type and ERCC-1 complemented cells. It is shown that NER de®cient cells are dramatically hypersensitive to UV-C induced apoptosis, indicating that DNA damage is the major stimulus for the apoptotic response. Apoptosis triggered by UV-C induced DNA damage is related to caspase-and proteosome-dependent degradation of Bcl-2 protein. The expression of other members of the Bcl-2 family such as Bax, Bcl-x L and Bak were not a ected. Bcl-2 decline is causally involved in UV-C induced apoptosis since overexpression of Bcl-2 protected NER de®cient cells against apoptosis. We also demonstrate that caspase-8, caspase-9 and caspase-3 are activated and PARP is cleaved in response to unrepaired UV-C induced DNA damage. Caspase-8 activation occurred independently of CD95 receptor activation since CD95R/ FasR and CD95L/FasL were not altered in expression, and transfection of transdominant negative FADD failed to block apoptosis. Overall, the data demonstrate that UV-C induced non-repaired DNA damage triggers apoptosis in NER de®cient ®broblasts involving components of the intrinsic mitochondrial damage pathway. Oncogene (2001) 20, 6026 ± 6038.

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Section: Discussionmentioning

confidence: 98%

Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation

Dunkern¹,

Fritz²,

Kaina³

2001

Oncogene

105

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“…These reports concluded that moderate doses of ionizing radiation inhibit initiation of DNA synthesis rather than suppression of replication fork progression. However, all of the cell lines used in these studies were either p53 deficient or p53 mutated (Storer et al, 1997;Hu et al, 1999;Bohnke et al, 2004). Therefore, the lowdose specificity and p53 dependency of the suppression of replication fork progression may well have been overlooked.…”

Section: Discussionmentioning

confidence: 99%

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

et al. 2006

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The S-phase DNA damage checkpoint is activated by DNA damage to delay DNA synthesis allowing time to resolve the replication block. We previously discovered the p53-dependent S-phase DNA damage checkpoint in mouse zygotes fertilized with irradiated sperm. Here, we report that the same p53 dependency holds in mouse embryonic fibroblasts (MEFs) at low doses of irradiation. DNA synthesis in p53 wild-type (WT) MEFs was suppressed in a biphasic manner in which a sharp decrease below 2.5 Gy was followed by a more moderate decrease up to 10 Gy. In contrast, p53À/À MEFs exhibited radioresistant DNA synthesis below 2.5 Gy whereas the cells retained the moderate suppression above 5 Gy. DNA fiber analysis revealed that 1 Gy irradiation suppressed replication fork progression in p53 WT MEFs, but not in p53À/À MEFs. Proliferating cell nuclear antigen (PCNA), clamp loader of DNA polymerase, was phosphorylated in WT MEFs after 1 Gy irradiation and redistributed to form foci in the nuclei. In contrast, PCNA was not phosphorylated and dissociated from chromatin in 1 Gy-irradiated p53À/À MEFs. These results demonstrate that the novel low-dosespecific p53-dependent S-phase DNA damage checkpoint is likely to regulate the replication fork movement through phosphorylation of PCNA.

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“…It is important to note that CHO-9 cells possess mutated p53 (Orren et al, 1995;Lee et al, 1997;Hu et al, 1999) and do not show transactivation of a p53-driven promoter (Dunkern and Kaina, unpublished data). Also, p21 was constitutively expressed in the cells without any further rise after GCV treatment (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Ganciclovir-induced apoptosis in HSV-1 thymidine kinase expressing cells: critical role of DNA breaks, Bcl-2 decline and caspase-9 activation

Thust²,

2002

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Characterization of p53 in Chinese hamster cell lines CHO-K1, CHO-WBL, and CHL: implications for genotoxicity testing

Cited by 102 publications

References 29 publications

Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation

Ultraviolet light-induced DNA damage triggers apoptosis in nucleotide excision repair-deficient cells via Bcl-2 decline and caspase-3/-8 activation

Suppression of replication fork progression in low-dose-specific p53-dependent S-phase DNA damage checkpoint

Ganciclovir-induced apoptosis in HSV-1 thymidine kinase expressing cells: critical role of DNA breaks, Bcl-2 decline and caspase-9 activation

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