The Role of CDC25A in Ultraviolet-induced Nonmelanoma Skin Tumorigenesis

Cell division cycle 25A (CDC25A) is a dual-specificity phosphatase that removes inhibitory phosphate groups from cyclin-dependent kinases, allowing cell cycle progression. Activation of cell cycle checkpoints following DNA damage can result in degradation of CDC25A, leading to cell cycle arrest. Consistent with its role in cell cycle regulation, CDC25A is over-expressed in multiple types of human cancer. Ultraviolet (UV) irradiation, which causes most skin cancer, results in both DNA damage and CDC25A degradation. In order to investigate the role of CDC25A in the skin’s response to UV, we conditionally ablated Cdc25a in the skin by crossing Cdc25afl/fl mice with transgenic Krt14 promoter-driven Cre recombinase mice. We hypothesized that ablation of CDC25A in the skin would increase cell cycle arrest following UV irradiation, allowing for improved repair of DNA damage and decreasing tumorigenesis. UV-induced DNA damage, in the form of cyclopyrimidine dimers and 8-oxo-deoxyguanosine adducts was eliminated earlier in the Cdc25a mutant skin when compared to the UV-exposed controls. Surprisingly, no significant difference in cell cycle regulation after UV exposure was detected in the mutants compared to controls. However, apoptosis was increased in the Cdc25a mutants compared to controls 18 hours following UV exposure. Deletion of Cdc25a resulted in increased epidermal hyperplasia compared to controls at 36 h post-UV. Although there was no difference in tumor multiplicity, UV-induced papillomas in Tg.AC+/Cdc25a mutants were significantly smaller than in controls in the first 6 weeks following UV exposure. These data suggest that loss of CDC25A facilitates the rapid repair of DNA damage through increased apoptosis of damaged cells following exposure to UV, but has surprisingly little effect on cell cycle regulation. Interestingly, improved repair of DNA damage did not result in decreased tumorigenesis. The number of tumors was similar in Cdc25a mutant and control mice, although tumors were smaller in the mutants. Thus, in this model, deletion of Cdc25a improved the repair of DNA damage and increased apoptosis following UV, but did not substantially alter cell cycle regulation. The cumulative effects of CDC25A deletion in UV-exposed skin did not alter tumor multiplicity in a v-rasHa transgenic model but did result in smaller tumors.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2010

Author dc:creator

• Yanagida, Jodi Keiko Hirata

Advisor dc:contributor.advisor

• Hansen, Laura A.

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10504/16011

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/16011