GSK-3 Represses Growth Factor-inducible Genes by Inhibiting NF-kappa B in Quiescent Cells

作者：Graham Julie R; Tullai John W; Cooper Geoffrey M^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285(7): 4472-4480.

DOI：10.1074/jbc.M109.053785

GSK-3 is active in the absence of growth factor stimulation and generally acts to induce apoptosis or inhibit cell proliferation. We previously identified a subset of growth factor-inducible genes that can also be induced in quiescent T98G cells solely by inhibition of GSK-3 in the absence of growth factor stimulation. Computational predictions verified by chromatin immunoprecipitation assays identified NF-kappa B binding sites in the upstream regions of 75% of the genes regulated by GSK-3. p50 bound to most of these sites in quiescent cells, and for one-third of the genes, binding of p65 to the predicted sites increased upon inhibition of GSK-3. The functional role of p65 in gene induction following inhibition of GSK-3 was demonstrated by RNA interference experiments. Furthermore, inhibition of GSK-3 in quiescent cells resulted in activation of I kappa B kinase, leading to phosphorylation and degradation of I kappa B alpha and nuclear translocation of p65 and p50. Taken together, these results indicate that the high levels of GSK-3 activity in quiescent cells repress gene expression by negatively regulating NF-kappa B through inhibition of I kappa B kinase. This inhibition of NF-kappa B is consistent with the role of GSK-3 in the induction of apoptosis or cell cycle arrest in cells deprived of growth factors.

• 出版日期2010-2-12