While the growth arrest and DNA damage-inducible gene Gadd45a is generally perceived as a p53-effector gene, it has now been shown to be a key regulator of the guardian of the genome, p53, via a positive feedback loop involving the stress MAP-kinase (MAPK) signaling cascade. Gadd45a-deficient mice are unable to maintain MAPK activation in the skin after UV irradiation, which is required for normal p53 activation. This in effect places Gadd45a upstream of p53 and the stress MAPKs. Consequently, the acute cutaneous effects observed in mice lacking p53 are also observed in Gadd45a-deficient mice, such as reduced sunburn (apoptotic) cells and defective cell cycle checkpoints after UV radiation. In the end, chronically irradiated mice are at significant risk for developing non-melanoma skin cancer in the absence of Gadd45a. Shown here is a representative H&E section of a squamous cell carcinoma invading the dermis of chronically UV-irradiated Gadd45a-null mice. The tumor is composed of whorls of atypical stratified squamous epithelia cells with central keratinization. For details, see the article by Hildesheim et al. on page 7305 of this issue.

[Table of Contents]