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United States Department of Agriculture

Agricultural Research Service

Research Project: Dietary Modulation of Immune Function and Oxidative Stress

Location: Immunity and Disease Prevention Research Unit

Title: Delayed cell cycle progression from SEPW1 depletion is p53- and p21-dependent in MCF-7 breast cancer cells

Authors
item HAWKES, CHRIS
item ALKAN, ZEYNEP

Submitted to: Biochemical and Biophysical Research Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 5, 2011
Publication Date: September 7, 2011
Citation: Hawkes, W.C., Alkan, Z. 2011. Delayed cell cycle progression from SEPW1 depletion is p53- and p21-dependent in MCF-7 breast cancer cells. Biochemical and Biophysical Research Communications. doi:10.1016/j.bbrc.2011.08.032.

Interpretive Summary: Selenium has been associated with cancer prevention and treatment for almost a century. Our previous work showed that a small selenium-containing protein, selenoprotein W, controlled entry into the cell division cycle in non-cancerous breast and prostate cells and that it worked by regulating the stability of the p53 tumor suppressor protein. Because uncontrolled cell division is a hallmark of cancer and p53 is the most frequently mutated gene in human cancers, it was important to understand how selenoprotein W worked. We showed that selenoprotein W controlled entry into the cell division cycle in human breast cancer cells and did so by adding a phosphate group onto the p53 protein. We found that cell cycle control by selenoprotein W also required another cell cycle regulator known as p21 that is controlled by p53. Our data suggest that selenoprotein W is not an antioxidant as previously proposed. This work will help understand the role of dietary selenium in cancer prevention. This is important because the recent SELECT trial failed to find any cancer protection from selenium supplements but instead found an increased risk of Type II diabetes. Only from a thorough knowledge the functions of the biologically active selenium-containing proteins will we be able to understand how and why dietary selenium affects the risk of cancer and other chronic diseases.

Technical Abstract: Selenium (Se) is an essential redox-active element with close connections to cancer. Most of Se’s biological functions have been attributed to the antioxidant properties of Se-containing proteins. The relative contribution of selenoproteins and small Se compounds in cancer protection is a matter of debate. The tumor suppressor p53 is the most frequently mutated gene in human cancer and is often referred to as the “guardian of the genome”. In response to genomic stresses, p53 causes cell cycle arrest to allow time for DNA to be repaired before cell division or induces apoptosis to eliminate irreparably damaged cells. Selenoprotein W (SEPW1) is a highly conserved small thioredoxin-like protein required for cell cycle progression. The present work shows that SEPW1 facilitates the G1 to S-phase transition by down-regulating expression of the cyclin-dependent kinase inhibitor p21. SEPW1 controls p21 by modulating stability of the p53 transcription factor, and this is associated with changes in phosphorylation of serine-33 in p53. SEPW1 depletion does not activate p53 via the DNA damage pathway, suggesting that antioxidant protection is not the primary function of SEPW1. More is needed to identify the mechanism by which SEPW1 regulates phosphorylation of serine-33 and the kinase or phosphatase enzymes involved.

Last Modified: 8/27/2014
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