ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis.

ABSTRACT: Rescue of the p53 tumor suppressor is an attractive cancer therapy approach. However, pharmacologically activated p53 can induce diverse responses ranging from cell death to growth arrest and DNA repair, which limits the efficient application of p53-reactivating drugs in clinic. Elucidation of the molecular mechanisms defining the biological outcome upon p53 activation remains a grand challenge in the p53 field. Here, we report that concurrent pharmacological activation of p53 and inhibition of thioredoxin reductase followed by generation of reactive oxygen species (ROS), result in the synthetic lethality in cancer cells. ROS promote the activation of c-Jun N-terminal kinase (JNK) and DNA damage response, which establishes a positive feedback loop with p53. This converts the p53-induced gr

SUBMITTER: Shi Y 

PROVIDER: S-EPMC3950324 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature