Regulation of cellular response to oncogenic and oxidative stress by Seladin-1

Expression of multiple oncogenes and inactivation of tumour suppressors is required to transform primary mammalian cells into cancer cells 1 , 2 , 3 . Activated Ha- RasV12 (Ras) is usually associated with cancer, but it also produces paradoxical premature senescence 4 in primary cells by inducing reactive oxygen species 5 followed by accumulation of tumour suppressors p53 and p16 INK4a (ref. 4 ). Here we identify, using a direct genetic screen, Seladin-1 (also known as Dhcr24 ) as a key mediator of Ras-induced senescence. Following oncogenic and oxidative stress, Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53, thus resulting in p53 accumulation. Additionally, Seladin-1 associates with Mdm2 independently of p53, potentially affecting other Mdm2 targets. Ablation of Seladin-1 causes the bypass of Ras-induced senescence in rodent and human fibroblasts, and allows Ras to transform these cells. Wild-type Seladin-1, but not mutants that disrupt its association with either p53 or Mdm2, suppresses the transformed phenotype. The same mutants are also inactive in directing p53-dependent oxidative stress response. These results show an unanticipated role for Seladin-1, previously implicated in Alzheimer's disease 6 and cholesterol metabolism 7 , in integrating cellular response to oncogenic and oxidative stress.