US EPA

2187009 

Journal Article 

Abstract 

ROS-signaling integrates cyclin D1 turnover to inhibition in entry into S-phase in PCB-153 treated MCF10A human non-malignant mammary epithelial cells 

Venkatesha, VA; Sarsour, EH; Goswami, PC 

2008 

Yes 

Free Radical Biology and Medicine
ISSN: 0891-5849
EISSN: 1873-4596 

45 

Suppl. 

S24-S24 

English 

WOS:000260867900060 

http://www.sciencedirect.com/science/article/pii/S0891584908006199
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is part of a larger document 3452652 SFRBM's 15th Annual Meeting: Program and Abstracts

PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) is a non-metabolizable environmental chemical contaminant commonly found in breast milk of PCB-exposed individuals suggesting that chronic exposure to PCB153 could have adverse health effects. We have previously shown that PCB153 treatment elevated reactive oxygen species (ROS) levels in MCF10A human non-malignant mammary epithelial cells that correlated with an inhibition in cell growth. This study investigates the hypothesis that a redoxsensitive and phosphorylation-dependent turnover of cyclin D1 inhibits entry into S-phase. MCF10A cells treated with PCB153 for 4h showed a biphasic response, increased cyclin D1 levels in 1 µM PCB153 treated cells compared to more than 70% decrease in 10-20 µM PCB153 treated cells. the half-life of cyclin D1 was 70 min in 1 µM and 20 min in 10 µM PCB treated cells compared to 30 min in control. PCB153 induced changes in cyclin D1 was associated with increases in GSK-3-beta phosphorylation and decrease in Rb protein levels. Prior treatment of cells with MG132 inhibited PCB153 induced decrease in cyclin D1 protein levels suggesting that the proteasome pathway could degrade cyclin D1 in PCB153 treated cells. Interestingly, PCB153 induced degradation in cyclin D1 was absent in mouse fibroblasts carrying a mutant for m of cyclin D1 (T286A) indicating that the PCB153 induced degradation of cyclin D1 could be mediated via the T286 phosphorylation pathway. MCF10A cells treated with catalase and tempol reversed PCB153 induced decrease in cyclin D1 protein levels. PCB153 induced cyclin D1 degradation inhibited cells entry into S-phase by more than 90%. These results support the novel hypothesis that a redox-sensitive regulation of cyclin D1 protein levels regulates entry into S-phase in PCB153 treated MCF10A cells. (NIEHS P42 ES 013661 and NIH CA 111365). 

Society for Free Radical Biology and Medicine 15th Annual Meeting 

Indianapolis, IN 

November 19-23, 2008