Abstract
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-kappaB 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 IkappaB kinase, leading to phosphorylation and degradation of IkappaB 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-kappaB through inhibition of IkappaB kinase. This inhibition of NF-kappaB is consistent with the role of GSK-3 in the induction of apoptosis or cell cycle arrest in cells deprived of growth factors.
Highlights
Grant R01 CA18689. □S The on-line version of this article contains supplemental Table S1. 1 To whom correspondence should be addressed: 5 Cummington St., Boston, Unlike most protein kinases, Glycogen synthase kinase-3 (GSK-3) is active in the absence of growth factor stimulation and generally acts to inhibit cell proliferation or induce apoptosis [1,2,3,4,5]
The fact that GSK-3 is active in the absence of growth factor stimulation suggests that it may play a role in regulating gene expression in quiescent cells
Computational analysis identified binding sites for the transcription factor CREB as highly over-represented in the upstream regions of the GSK-3-regulated genes, and subsequent chromatin immunoprecipitation and siRNA experiments indicated that inhibition of CREB by GSK-3 plays an important role in repressing transcription of these genes in quiescent cells [12]
Summary
Grant R01 CA18689. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1. 1 To whom correspondence should be addressed: 5 Cummington St., Boston, Unlike most protein kinases, GSK-3 is active in the absence of growth factor stimulation and generally acts to inhibit cell proliferation or induce apoptosis [1,2,3,4,5]. The fact that GSK-3 is active in the absence of growth factor stimulation suggests that it may play a role in regulating gene expression in quiescent cells.
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