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PMID:15166087
| Citation |
Young, LC, Thulien, KJ, Campbell, MR, Tron, VA and Andrew, SE (2004) DNA mismatch repair proteins promote apoptosis and suppress tumorigenesis in response to UVB irradiation: an in vivo study. Carcinogenesis 25:1821-7 |
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| Abstract |
DNA mismatch repair (MMR) proteins are integral to the maintenance of genomic stability and suppression of tumorigenesis due to their role in repair of post-replicative DNA errors. Recent data also support a role for MMR proteins in cellular responses to exogenous DNA damage that does not involve removal of DNA adducts. We have demonstrated previously that both Msh2- and Msh6-null primary mouse embryonic fibroblasts are significantly less sensitive to UVB (ultraviolet B)-induced cytotoxicity and apoptosis than wild-type control cells. In order to ascertain the physiological relevance of the data we have exposed MMR-deficient mice to acute and chronic UVB radiation. We found that MMR-deficiency was associated with reduced levels of apoptosis and increased residual UVB-induced DNA adducts in the epidermis 24-h following acute UVB exposure. Moreover, Msh2-null mice developed UVB-induced skin tumors at a lower level of cumulative UVB exposure and with a greater severity of onset than wild-type mice. The Msh2-null skin tumors did not display microsatellite instability, suggesting that these tumors develop via a different tumorigenic pathway than tumors that develop spontaneously. Therefore, we propose that dysfunctional MMR promotes UVB-induced tumorigenesis through reduced apoptotic elimination of damaged epidermal cells. |
| Links |
PubMed Online version:10.1093/carcin/bgh191 |
| Keywords |
Animals; Apoptosis/radiation effects; Carcinoma, Squamous Cell/metabolism; Carcinoma, Squamous Cell/pathology; DNA Adducts; DNA Repair/radiation effects; DNA-Binding Proteins/genetics; DNA-Binding Proteins/physiology; Epidermis/cytology; Epidermis/physiology; Epidermis/radiation effects; Humans; Mice; Mice, Knockout; Microsatellite Repeats; MutS Homolog 2 Protein; Neoplasm Invasiveness/pathology; Neoplasms, Radiation-Induced/metabolism; Neoplasms, Radiation-Induced/pathology; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/physiology; Pyrimidine Dimers; Skin Neoplasms/metabolism; Skin Neoplasms/pathology; Ultraviolet Rays |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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See also
References
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