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High glucose inhibits p53 function via Thr55 phosphorylation
Author(s) -
Wu Yong,
Lin Joy,
Piluso Landon G.,
Liu Xuan
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.503.5
Subject(s) - phosphorylation , chemistry , transfection , kinase , microbiology and biotechnology , cancer research , biochemistry , biology , gene
Emerging evidence has begun to indicate that elevated glucose levels increase the risk for developing cancer. However, molecular mechanisms for this risk are largely undefined. Here we show that exposure of U2OS cells to high glucose (HG) but not its analog 2‐deoxyglucose increased cellular ATP levels and inhibited p21 expression. Further, HG suppressed p21 expression in HCT116p53+/+ but not HCT116p53−/− cells, implying that the inhibitory effects of HG might be dependent of p53. To define the molecular mechanisms, we show that HG stimulated TAF1 kinase activity and resultant p53 Thr55 phosphorylation, leading to p53 degradation and decreased p21 expression. Inhibition of TAF1 activity with apigenin abolished HG‐induced Thr55 phosphorylation, p53 protein degradation and inhibition of p21 expression suggesting that Thr55 plays a role in HG‐induced p21 inhibition. In addition, HG suppressed p21 expression in H1299 cells transfected with wild type p53 (H1299‐p53) but not with T55A (H1299‐T55A). Moreover, HG‐induced inhibition of p21 was blocked by apigenin in H1299‐p53 but not H1299‐T55A indicating that TAF1‐mediated Thr55 phosphorylation was involved in HG‐induced p21 inhibition. We conclude that HG inhibits p53 function, at least in part, via ATP overproduction/TAF1‐mediated Thr55 phosphorylation. This observation may provide a mechanistic explanation for the association between diabetes and cancer.