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Gadd45a Protects against UV Irradiation-induced Skin Tumors, and Promotes Apoptosis and Stress Signaling via MAPK and p53^{1 ,2}

Gene Response Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255 [J. H., D. V. B., M. C. H., L. V., A. J. F.]; Pathology/Histotechnology Laboratory, Science Applications International Corp., Frederick, Maryland 21702-1201 [M. R. A.]; and Data Management Services, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201 [W. G. A.]

Skin cancer is the most frequent form of malignancy in the world, and UV radiation is the primaryenvironmental carcinogen responsible for its development. Herein we demonstratethat Gadd45a is a critical factor protecting the epidermis against UV radiation-induced tumorigenesis by promoting damaged keratinocytes to undergo apoptosis and/or cell cycle arrest, two crucial events that prevent the expansion of mutant or deregulated cells. Whereas Gadd45a has been implicated in cell cycle arrest, apoptosis, and DNA repair, to determine the physiological function of endogenous Gadd45a after genotoxic stress, the skin of Gadd45a-null mice was targeted with UV radiation. We report that Gadd45a induces apoptosis and cell cycle arrest by maintaining p38 and c-JNK MAPK activation in keratinocytes. The absence of Gadd45a results in loss of sustained p38/JNK MAPK activity beyond 15–30 min after UV radiation that leads to inadequate p53 activation and loss of normal activation of G₁ and G₂ checkpoints. Moreover, loss of Gadd45a dramatically reduces UV-induced apoptotic keratinocytes, "sunburn cells." Consequently, Gadd45a-null mice are more prone to tumors relative to wild-type mice. Therefore, we conclude that Gadd45a, like p53, is a key component protecting skin against UV-induced tumors.

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