Occupational exposure to mineral dusts, such as silica, has been associated with progressive pulmonary inflammation, lung cancer, and fibrosis. However, the mechanisms involved in this process are poorly understood. Since p53 is a key transcription factor that regulates many important apoptosis-related genes, we hypothesized that p53 may play a key role in silica-induced apoptosis and that abnormal regulation of p53 by silica may contribute to development of lung cancer as well as silicosis. To test this hypothesis, both in vitro and in vivo studies were carried out. Treatment of JB6 cells carrying a p53-luciferase reporter plasmid with silica caused a dose dependent p53 trans-activation. Western Blot analysis indicated that silica not only stimulated p53 protein expression, but also caused phosphorylation of p53 at Serine 392 position. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and DNA fragmentation analysis showed that silica caused apoptosis in both JB6 cells and wild-type p53 (p53+/+) fibroblasts, but not in p53-deficient (p53-/-) fibroblasts. Similar results were obtained by in vivo studies. Intratracheal instillation of mice with silica induced apoptosis in the lung of p53 +/+ mice, whereas this induction was significantly inhibited in p53 -/- mice. Confocal image analysis indicated that the majority of apoptotic cell that induced by silica in the lung were alveolar macrophages. These results demonstrate for the first time that silica induces p53 transactivation via induction of p53 protein expression and phosphorylation of p53 protein, and that p53 plays a crucial role in the signal transduction pathways of silica-induced apoptosis. This finding may provide an important link in understanding the molecular mechanisms of silica-induced carcinogenesis and pathogenesis in the lung.