THE P53-DEPENDENT G(1) CELL-CYCLE CHECKPOINT PATHWAY AND ATAXIA-TELANGIECTASIA

The p53 protein is a critical participant in a signal transduction pat hway which mediates a G, cell cycle arrest and apoptotic cell death in mammalian cells after ionizing irradiation. Cells from patients with the cancer-prone, radiation-sensitive disorder, ataxia-telangiectasia (AT), exhibit suboptimal (delayed and/or defective) induction of p53 p rotein after ionizing radiation with some dependence on dose. Other pr otein products which participate in this signal transduction pathway, including p21(WAF1/CIP1), Gadd45, and Mdm2, are also suboptimally indu ced in AT cells after ionizing radiation. Induction of p53 is also abn ormal in AT cells following treatment with methylmethanesulfonate and bleomycin but appears relatively normal following treatment with W-C i rradiation or the topoisomerase inhibitors, etoposide and camptothecin . These results demonstrate a specific defect in this p53-dependent si gnal transduction pathway in AT cells. Potential models for this obser ved specificity of the AT defect as measured by p53 induction include problems with responses to: (a) single-strand, but not double-strand, DNA breaks; or (b) chemically, but not enzymatically, generated DNA en ds.