Protective effects of thioredoxin-mediated p53 activation in response to mild hyperthermia

Recently, mild hyperthermia was shown to induce cell cycle arrest at the G ₂/M phase transition without leading to DNA damage. The mechanism of this regulation has not yet been elucidated, although p53 has been shown to be activated in response to mild hyperthermia. Here, we report the role of thioredoxin (TXN) in mild hyperthermia-induced cellular responses. Our data showed that the protein levels of p53 and its downstream gene, Gadd45a, which is an indicator of G2/M arrest, were significantly decreased in TXN siRNA-treated cells under conditions of mild hyperthermia (41°C, 60 min) as compared to TXN wild-type cells, implying that TXN might play an important role in mild hyperthermia-induced G ₂/M arrest via p53 and Gadd45a activation. Furthermore, the release of cyclin-dependent kinase Cdc2, known to be regulated by Gadd45a under G ₂/M arrest, was inhibited from the nucleus for arrest in the G ₂/M phase in TXN downregulated cells under mild hyperthermia. We suggest that G ₂/M arrest mediated via the TXN-modulated p53 in response to mild hyperthermia may provide critical insight into the clinical use of mild hyperthermia to induce an adaptive response against genotoxic stresses.