AP-1 is a component of the transcriptional network regulated by GSK-3 in quiescent cells
Tullai, John W.
Owens, Laura J.
Graham, Julie R.
Cooper, Geoffrey M.
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Citation (published version)John W Tullai, Silvia Tacheva, Laura J Owens, Julie R Graham, Geoffrey M Cooper. 2011. "AP-1 Is a Component of the Transcriptional Network Regulated by GSK-3 in Quiescent Cells." PLOS ONE, Volume 6, Issue 5. https://doi.org/10.1371/journal.pone.0020150
BACKGROUND: The protein kinase GSK-3 is constitutively active in quiescent cells in the absence of growth factor signaling. Previously, we identified a set of genes that required GSK-3 to maintain their repression during quiescence. Computational analysis of the upstream sequences of these genes predicted transcription factor binding sites for CREB, NFκB and AP-1. In our previous work, contributions of CREB and NFκB were examined. In the current study, the AP-1 component of the signaling network in quiescent cells was explored. METHODOLOGY/PRINCIPAL FINDINGS: Using chromatin immunoprecipitation analysis, two AP-1 family members, c-Jun and JunD, bound to predicted upstream regulatory sequences in 8 of the 12 GSK-3-regulated genes. c-Jun was phosphorylated on threonine 239 by GSK-3 in quiescent cells, consistent with previous studies demonstrating inhibition of c-Jun by GSK-3. Inhibition of GSK-3 attenuated this phosphorylation, resulting in the stabilization of c-Jun. The association of c-Jun with its target sequences was increased by growth factor stimulation as well as by direct GSK-3 inhibition. The physiological role for c-Jun was also confirmed by siRNA inhibition of gene induction. CONCLUSIONS/SIGNIFICANCE: These results indicate that inhibition of c-Jun by GSK-3 contributes to the repression of growth factor-inducible genes in quiescent cells. Together, AP-1, CREB and NFκB form an integrated transcriptional network that is largely responsible for maintaining repression of target genes downstream of GSK-3 signaling.
Rights© 2011 Tullai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.