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AP-1 is a component of the transcriptional network regulated by GSK-3 in quiescent cells.

Tullai JW, Tacheva S, Owens LJ, Graham JR, Cooper GM - PLoS ONE (2011)

Bottom Line: Inhibition of GSK-3 attenuated this phosphorylation, resulting in the stabilization of c-Jun.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boston University, Boston, Massachusetts, United States of America.

ABSTRACT

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.

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Related in: MedlinePlus

Model of the GSK-3 transcriptional network in quiescent cells.The AP-1 data has been combined with that of CREB [10] and NFκB [12]. Both grey and black arrows indicate ChIP binding by the given factor to the gene's upstream sequence. Black arrows indicate that siRNA against the factor blocked induction of the gene in response to SB-216763 treatment greater than two-fold and statistically significant (p<0.05). The blunt-ended edge between AP-1 and NR4A1 indicates a greater than two-fold inhibition (p<0.05) of induction in the presence of AP-1. RND3 and CCL8 have been excluded from the illustration, as no ChIP binding nor transcription factor knockdown data indicated any functional connections with AP-1, NFκB or CREB.
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pone-0020150-g007: Model of the GSK-3 transcriptional network in quiescent cells.The AP-1 data has been combined with that of CREB [10] and NFκB [12]. Both grey and black arrows indicate ChIP binding by the given factor to the gene's upstream sequence. Black arrows indicate that siRNA against the factor blocked induction of the gene in response to SB-216763 treatment greater than two-fold and statistically significant (p<0.05). The blunt-ended edge between AP-1 and NR4A1 indicates a greater than two-fold inhibition (p<0.05) of induction in the presence of AP-1. RND3 and CCL8 have been excluded from the illustration, as no ChIP binding nor transcription factor knockdown data indicated any functional connections with AP-1, NFκB or CREB.

Mentions: The results of gene regulation downstream of GSK-3 by AP-1 are integrated with the results of our previous studies on CREB [10] and NFκB [12] in Figure 7. These 3 factors comprise a transcriptional network that maintains repression of growth factor-inducible genes in quiescent cells. Of 12 genes that were inducible by inhibition of GSK-3 in quiescent T98G cells, 10 were targeted by at least one of these three transcription factors. Moreover, 4 genes were targeted by all 3 transcription factors and 5 genes by 2 of the 3 factors.


AP-1 is a component of the transcriptional network regulated by GSK-3 in quiescent cells.

Tullai JW, Tacheva S, Owens LJ, Graham JR, Cooper GM - PLoS ONE (2011)

Model of the GSK-3 transcriptional network in quiescent cells.The AP-1 data has been combined with that of CREB [10] and NFκB [12]. Both grey and black arrows indicate ChIP binding by the given factor to the gene's upstream sequence. Black arrows indicate that siRNA against the factor blocked induction of the gene in response to SB-216763 treatment greater than two-fold and statistically significant (p<0.05). The blunt-ended edge between AP-1 and NR4A1 indicates a greater than two-fold inhibition (p<0.05) of induction in the presence of AP-1. RND3 and CCL8 have been excluded from the illustration, as no ChIP binding nor transcription factor knockdown data indicated any functional connections with AP-1, NFκB or CREB.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102068&req=5

pone-0020150-g007: Model of the GSK-3 transcriptional network in quiescent cells.The AP-1 data has been combined with that of CREB [10] and NFκB [12]. Both grey and black arrows indicate ChIP binding by the given factor to the gene's upstream sequence. Black arrows indicate that siRNA against the factor blocked induction of the gene in response to SB-216763 treatment greater than two-fold and statistically significant (p<0.05). The blunt-ended edge between AP-1 and NR4A1 indicates a greater than two-fold inhibition (p<0.05) of induction in the presence of AP-1. RND3 and CCL8 have been excluded from the illustration, as no ChIP binding nor transcription factor knockdown data indicated any functional connections with AP-1, NFκB or CREB.
Mentions: The results of gene regulation downstream of GSK-3 by AP-1 are integrated with the results of our previous studies on CREB [10] and NFκB [12] in Figure 7. These 3 factors comprise a transcriptional network that maintains repression of growth factor-inducible genes in quiescent cells. Of 12 genes that were inducible by inhibition of GSK-3 in quiescent T98G cells, 10 were targeted by at least one of these three transcription factors. Moreover, 4 genes were targeted by all 3 transcription factors and 5 genes by 2 of the 3 factors.

Bottom Line: Inhibition of GSK-3 attenuated this phosphorylation, resulting in the stabilization of c-Jun.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Boston University, Boston, Massachusetts, United States of America.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus