Selenoprotein W is required for epidermal growth factor (EGF)‐stimulated proliferation via a pathway involving MKK4 and p53

Selenoprotein W (SEPW1) is a highly conserved thioredoxin‐like protein whose depletion causes a p53‐ and p21‐dependent G1‐phase cell cycle arrest in breast and prostate epithelial cells. SEPW1 promotes the ubiquitination, nuclear export, and proteasomal degradation of p53, effects that are associated with decreased phosphorylation of Ser‐33 in p53. We now report that SEPW1 is required for EGF‐stimulated proliferation in breast and prostate cells. SEPW1 depletion blocked EGF‐stimulated G1 to S‐phase progression and altered signaling via downstream MAP kinase pathways. In an siRNA screen of 4 MAP kinase kinases and 6 MAP kinase kinase kinases, only silencing of MKK4 (JNKK1/SEK1) blocked G1 arrest, Ser‐33 phosphorylation, and p53 activation from SEPW1 depletion in EGF‐stimulated cells, suggesting MKK4 is downstream from SEPW1 in a p53‐dependent pathway regulating EGF‐stimulated cell cycle entry. We found that silencing p53 in freely cycling cells accelerated G1 to S‐phase progression, suggesting SEPW1 stimulates proliferation by suppressing the already low basal level of p53 expression. Taken together, these results suggest SEPW1 mediates EGF‐stimulated proliferation, at least in part, by suppression of p53 via MKK4, and presumably, one or more downstream MAP kinases. This research was supported by USDA CRIS Project 5306‐51530‐018‐00D. USDA is an equal opportunity provider and employer.