Gadd45a Prevents Skin Tumors by Watching Over p53

Researchers from the National Cancer Institute have identified a critical role for a gene known as Gadd45a (short for growth arrest and DNA damage-inducible gene), which protects the skin against cancer-causing damage from the sun's rays. In a study published Dec. 15, 2002, in Cancer Research*, researchers show that mice without Gadd45a develop a high rate of skin tumors when exposed to ultraviolet (UV) light similar to that from the sun. The study demonstrates that Gadd45a prevents skin tumors in mice by regulating the most commonly mutated gene in human tumors, p53. This important role in the cellular response to DNA damage suggests Gadd45a may be a useful target for future cancer therapies.

UV light from the sun and other sources can damage DNA, and growth of a cell containing DNA errors can lead to tumor development. Both Gadd45a and p53 are essential to cells' innate strategy to remove cells with damaged DNA. Normal cells respond to DNA damage either by stopping growth until the errors can be repaired or committing cell suicide. Both responses ensure that inaccuracies in DNA are not propagated in new cells.

Due to its critical role in this process, p53 is considered the key protector of cells' genetic material, but in the new study researchers found that cells required Gadd45a to maintain activation of p53 and respond normally to DNA damage. "Although p53 is often thought of as the guardian of the genome, we have now identified Gadd45a as its superior," noted Jeffrey Hildesheim, Ph.D., the first author of the study.

Mice in the study were regularly exposed to UV light over a period of one year, and those lacking the Gadd45a gene developed significantly more skin tumors than normal mice. The high number of tumors correlated with a failure of cells to respond normally to damaged DNA. Normal mice experience sunburn in response to exposure to UV light, indicating that cells are dying to prevent passing on damaged genes. Sunburn did not, however, occur in mice without Gadd45a. Similarly, cells without Gadd45a did not stop growing after exposure to UV light to allow for DNA repair.

Cellular damage from UV light is known to contribute to the more than 1.3 million cases of non-melanoma skin cancer diagnosed annually in the United States. Researchers hope that understanding the pathways leading to tumor development will elucidate targets for intervention against this disease. Furthermore, mutations in Gadd45a have been found frequently in pancreatic cancers, suggesting that Gadd45a may be key to cancer progression in general.

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* Hildesheim, J., Bulavin, D.V., Anver, M.R., Alvord, W.G., Hollander, M.C., Vardanian, L., & Fornace, A.J. (2002). Gadd45a protects against UV irradition-induced skin tumors and promotes apoptosis and stress signaling via MAP kinases and p53. Cancer Research, 62, 7305-7315.