DIETARY MODULATION OF IMMUNE FUNCTION AND OXIDATIVE STRESS
Location: Immunity and Disease Prevention Research Unit
Title: Selenoprotein W depletion induces a p53- and p21-dependent delay in cell cycle progression in RWPE-1 prostate epithelial cells
Submitted to: Journal of Cellular Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 12, 2011
Publication Date: January 1, 2012
Citation: Hawkes, W.C., Alkan, Z. 2012. Selenoprotein W depletion induces a p53- and p21-dependent delay in cell cycle progression in RWPE-1 prostate epithelial cells. Journal of Cellular Biochemistry. 113:61-69.
Interpretive Summary: Selenium is the nutrient with the greatest amount of evidence supporting a cancer-protective function, based on hundreds of animal and cell culture experiments showing positive results. However, the results from human trials of selenium supplementation have been mixed, with some studies showing a protective effect, others showing no protection, and some suggesting risk. This confusing situation highlights the need to understand the underlying mechanisms.
Selenium is an essential component of 25 human proteins, fewer than half of which have known functions. Many of the known selenoproteins have functions closely connected to processes important to cancer, but none have been found that explain selenium’s cancer-protective effect. We recently showed that Selenoprotein W, previously of unknown function, modulates control of cell division; dysfunctions of which are a main cause of cancer. In the present report, we show how Selenoprotein W regulates the tumor suppressor protein p53, known as the “Guardian of the genome” because it is disabled in every type of cancer.
Our work suggests that p53 is only one of a multitude of targets of Selenoprotein W and that the full spectrum of Selenoprotein W’s effects is only hinted at by the present work. Selenoprotein W is the most highly conserved and most highly distributed selenoprotein in Nature, implying it is also the most ancient selenoprotein. Thus, we expect to reveal many more aspects of selenium’s cancer-protective function in our further studies of Selenoprotein W.
The anticancer activity of selenium (Se) has been demonstrated in myriad animal and in vitro studies, yet the mechanisms remain obscure. The relative importance of small selenium compounds versus selenoproteins in the cancer-protective activity of Se is unresolved, but the main form of Se in animal tissues is selenocysteine (Sec) in selenoproteins. Selenoprotein W (SEPW1) is a highly conserved protein of unknown function ubiquitously expressed in animals, bacteria and archea that modulates control of cell cycle entry. Tumor suppressor protein p53, known as the “guardian of the genome”, is the master regulator of cell cycle entry and the most frequently mutated gene in human cancers. p53 was increased in cells growth-arrested by siRNA-mediated SEPW1 silencing and p53 was inversely related to SEPW1 mRNA in cell lines stably over-expressing or under-expressing SEPW1. Increased p53 protein levels in SEPW1-silenced cells resulted from increased p53 half-life, indicating that SEPW1 destabilizes p53. SEPW1 silencing dramatically increased p21 (Cip1/WAF1/CDKN1A), the cyclin-dependent kinase inhibitor responsible for p53-mediated G1 arrest, while p27 (Kip1, CDKN1B) levels were unaffected. Cell cycle arrest from SEPW1 knockdown was abolished by silencing the p21 gene, confirming the essential role of p21 in cell cycle regulation by SEPW1. Destabilization of p53 by SEPW1 was not associated with changes in phosphorylation of Ser15, a major site of p53 regulation in the canonical DNA damage response pathway. More research is required to identify the mechanisms by which SEPW1 destabilizes p53.