Cell Cycle Arrest From Selenoprotein W Depletion Is Mediated By P38 Map Kinase And Requires Intact Centrosomes

Selenoprotein W (SEPW1) is a widely expressed and highly conserved thioredoxin-like protein of unknown function. Our prior work showed that SEPW1 depletion with small inhibitory RNA (siRNA) caused a p53- and p21-dependent G1-phase cell cycle arrest in breast and prostate epithelial cells. We now report that in SEPW1-depleted cells p53 is stabilized by phosphorylation of Ser-33 and Ser-46 and accumulates in the nucleus. Ser-33 and Ser-46 are known sites in p53 for phosphorylation by p38 MAP kinase. Cell cycle arrest from SEPW1 depletion is abrogated by SB203580, a specific inhibitor of p38. Furthermore, cell cycle arrest and Ser-33 phosphorylation from SEPW1 depletion are attenuated by siRNA targeting p38-alpha. Thus, cell cycle arrest from SEPW1 depletion is at least partly mediated through p38-directed phosphorylation of p53. Silencing of centrosomal proteins pericentrin, PCM1, or TUBGCP5 blocks cell cycle arrest from SEPW1 depletion, suggesting involvement of a centrosome-based process. Disruption of centrosomal structure is known to cause a p38-p53-p21 dependent G1 arrest in what may constitute a centrosome duplication checkpoint in the cell cycle. These results point to the possibility of a previously unsuspected role of SEPW1 in centrosome structure, duplication, or function. This research was supported by USDA CRIS Project 5306-51530-018-00D. USDA is an equal opportunity provider and employer.