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. Activated Ha-RasV12 (Ras) is usually associated with cancer, but it also produces paradoxical premature senescence in primary cells by inducing reactive oxygen species 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 and cholesterol metabolism, in integrating cellular response to oncogenic and oxidative stress.
Wu
Chaowei
C
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Miloslavskaya
Irene
I
Demontis
Silvia
S
Maestro
Roberta
R
Galaktionov
Konstantin
K
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D005347:Fibroblasts; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D044925:Oxidoreductases Acting on CH-CH Group Donors; C437069:3beta-hydroxysterol delta24-reductase; C499055:DHCR24 protein, human; C497206:MDM2 protein, human; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; D015689:Oncogene Protein p21(ras)