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ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Publications at this Location » Publication #274856
Title: A role for p53 in selenium-induced senescence

Author
item WU, MIN - University Of Maryland
item WU, RYAN T.Y. - University Of Maryland
item Wang, Thomas - Tom
item CHENG, WEN-HSING - University Of Maryland

Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/2011
Publication Date: 11/9/2011
Citation: Wu, M., Wu, R., Wang, T.T., Cheng, W. 2011. A role for p53 in selenium-induced senescence. Journal of Agricultural and Food Chemistry. 591:1182-1187.

Interpretive Summary: The mechanisms underlying the biological effects of the micronutrient selenium and selenium containing compounds remain unclear. The role of the tumor suppressor protein p53 in mediating the biological activity of selenium in a cell culture model was investigated in collaboration with scientists from the University of Maryland. The tumor suppressor p53 and the ataxia-telangiectasia mutated (ATM) kinase play important roles in the senescence response to oncogene activation and DNA damage. We have previously shown that selenium-containing compounds can activate an ATM-dependent senescence response in MRC-5 normal fibroblasts in cell culture. Here, we employed a molecular shRNA knockdown approach and other DNA damage assays to test the hypothesis that p53 plays a role in selenium-induced senescence. In MRC-5 cells treated with methylseleninic acid (MSeA), depletion of p53 hampered senescence-associated expression of ß-galactosidase, disrupted cell cycle arrest, desensitized the cells to MSeA treatment, and increased genome instability. Pre-treatment with KU55933, an ATM kinase inhibitor, or NU7026, an inhibitor of DNA-dependent protein kinase, desensitized MSe cytotoxicity in scrambled but not p53 shRNA MRC-5 cells. These results suggested that p53 is critical for senescence induction in the response of MRC-5 non-cancerous cells to selenium compounds. This work provides novel information on the mechanism of action of selenium containing compounds in the response of cells to stressors, and will benefit basic as well as translational research science.

Technical Abstract: The tumor suppressor p53 and the ataxia-telangiectasia mutated (ATM) kinase play important roles in the senescence response to oncogene activation and DNA damage. We have previously shown that selenium-containing compounds can activate an ATM-dependent senescence response in MRC-5 normal fibroblasts. Here, we employ shRNA knockdown approach and other DNA damage assays to test the hypothesis that p53 plays a role in selenium-induced senescence. In MRC-5 cells treated with methylseleninic acid (MSeA, 0-10 µM), depletion of p53 hampers senescence-associated expression of ß-galactosidase, disrupts the otherwise S and G2/M cell cycle arrest, desensitizes such cells to MSeA treatment, and increases genome instability. Pre-treatment with KU55933, an ATM kinase inhibitor, or NU7026, an inhibitor of DNA-dependent protein kinase, desensitizes MSe cytotoxicity in scrambled but not p53 shRNA MRC-5 cells. These results suggest that p53 is critical for senescence induction in the response of MRC-5 non-cancerous cells to selenium compounds.