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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Immunity and Disease Prevention Research » Research » Publications at this Location » Publication #277579

Title: Delayed cell cycle progression in selenoprotein W depleted cells is regulated by a mitogen-activated protein kinase kinase 4–p38–p53 pathway

item Hawkes, Wayne
item Alkan, Zeynep

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/22/2012
Publication Date: 6/22/2012
Citation: Hawkes, W.C., Alkan, Z. 2012. Delayed cell cycle progression in selenoprotein W depleted cells is regulated by a mitogen-activated protein kinase kinase 4–p38–p53 pathway. Journal of Biological Chemistry. DOI: 10.1074/jbc.M112.346593.

Interpretive Summary: There is much controversy whether dietary selenium protects against cancer or actually makes cancer worse. It is critical to understand how selenium affects cell growth in order to sort this out. Dietary selenium supplements increase selenoprotein W more than any other selenoprotein, so we think it may be largely responsible for the effects of supplements. We discovered that selenoprotein W allows entry to the cell division cycle by suppressing the MKK4 protein that controls activation of the p53 tumor suppressor protein. A fuller understanding of this pathway may lead to nutritional supplements to effectively and safely prevent cancer or to development of improved cancer drugs.

Technical Abstract: Selenoprotein W (SEPW1) is a ubiquitous, highly conserved thioredoxin-like protein whose depletion causes a p53- and p21Cip1-dependent G1-phase cell cycle arrest in breast and prostate epithelial cells. SEPW1 depletion increases phosphorylation of Ser33 in p53, which is associated with decreased p53 ubiquitination and stabilization of p53. We report here that delayed cell cycle progression, Ser33 phosphorylation and p53 nuclear accumulation from SEPW1 depletion are mediated by a MKK4-p38 gamma/delta-p53 signaling pathway. Silencing MKK4 abrogated G1 arrest, Ser33 phosphorylation and nuclear accumulation of p53 from SEPW1 silencing. Silencing MKK3, MKK6, or MKK7 had no effect. SEPW1 silencing did not change phosphorylation of MKK4 and silencing six MAPK kinase kinases upstream of MKK4 had no effect on G1 arrest from SEPW1 silencing. Total MKK4 protein was increased by SEPW1 silencing, but MKK4 mRNA and MKK4 turnover were unchanged, suggesting SEPW1 silencing increases the rate of MKK4 translation. Silencing p38 gamma or p38 delta blocked G1 arrest from SEPW1 silencing, suggesting they have a dominant role signaling downstream from MKK4. These results suggest that SEPW1 silencing increases MKK4, which activates p38 gamma and p38 delta to phosphorylate p53 on Ser33 and cause G1 arrest.