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CELLULAR AND MOLECULAR

Beryllium Induces Premature Senescence in Human Fibroblasts

Department of Chemistry, University of Nevada, Las Vegas, Las Vegas, Nevada (S.S.A.C., S.M.K., R.K.G.); Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico (B.E.L.); and Nevada Cancer Institute, Las Vegas, Nevada (S.S.)

After cells have completed a sufficient number of cell divisions, they exit the cell cycle and enter replicative senescence. Here, we report that beryllium causes proliferation arrest with premature expression of the principal markers of senescence. After young presenescent human fibroblasts were treated with 3 µM BeSO₄ for 24 h, p21 cyclin-dependent kinase inhibitor mRNA increased by >200%. Longer periods of exposure caused mRNA and protein levels to increase for both p21 and p16(Ink4a), a senescence regulator that prevents pRb-mediated cell cycle progression. BeSO₄ also caused dose-dependent induction of senescence-associated -galactosidase activity (SA--gal). Untreated cells had 48 relative fluorescence units (RFU)/µg/h of SA--gal, whereas 3 µM BeSO₄ caused activity to increase to 84 RFU/µg/h. In chromatin immunoprecipitation experiments, BeSO₄ caused p53 protein to associate with its DNA binding site in the promoter region of the p21 gene, indicating that p53 transcriptional activity is responsible for the large increase in p21 mRNA elicited by beryllium. Forced expression of human telomerase reverse transcriptase (hTERT) rendered HFL-1 cells incapable of normal replicative senescence. However, there was no difference in the responsiveness of normal HFL-1 fibroblasts (IC₅₀ = 1.9 µM) and hTERT-immortalized cells (IC₅₀ = 1.7 µM) to BeSO₄ in a 9-day proliferation assay. The effects of beryllium resemble those of histone deacetylase-inhibiting drugs, which also cause large increases in p21. However, beryllium produced no changes in histone acetylation, suggesting that Be²⁺ acts as a novel and potent pharmacological inducer of premature senescence.

Address correspondence to: Dr. Ronald K. Gary, Department of Chemistry, University of Nevada, Las Vegas, 4505 Maryland Parkway, Las Vegas, NV 89154-4003. E-mail: ronald.gary{at}unlv.edu