c-Jun localizes to the nucleus independent of its phosphorylation by and interaction with JNK and vice versa promotes nuclear accumulation of JNK

Schreck, Ilona; Al‐Rawi, Marco; Mingot, José-Manuel; Scholl, Christine; Diefenbacher, Markus E.; O’Donnell, Paul; Bohmann, Dirk; Weiss, Carsten

doi:10.1016/j.bbrc.2011.03.092

Cited by 36 publications

(31 citation statements)

References 17 publications

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“…46 AP-1 is a homo-or heterodimer consisting of proteins belonging to the c-Jun, c-Fos, ATF and JDP families, 47 with c-Jun being the best-characterized AP-1 component. The nuclear import of c-Jun is mediated by multiple mechanisms 48,49 and nuclear c-Jun levels correlate with AP-1 target gene activity. 49 This further increases c-Jun protein abundance, as the jun proto-oncogene itself is activated by AP-1 in the manner of a positive auto-regulatory loop.…”

Section: Discussionmentioning

confidence: 99%

“…The nuclear import of c-Jun is mediated by multiple mechanisms 48,49 and nuclear c-Jun levels correlate with AP-1 target gene activity. 49 This further increases c-Jun protein abundance, as the jun proto-oncogene itself is activated by AP-1 in the manner of a positive auto-regulatory loop. 44 The activity of c-Jun/AP-1 is markedly enhanced by phosphorylation of the transcriptional activation domain by JNKs.…”

Section: Discussionmentioning

confidence: 99%

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Increased expression of c-Jun in nonalcoholic fatty liver disease

Dorn

Engelmann

Saugspier

et al. 2014

Laboratory Investigation

108

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Increased expression of c-Jun in nonalcoholic fatty liver disease

Dorn

Engelmann

Saugspier

et al. 2014

Laboratory Investigation

108

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“…For example, following coexpression with partners like c-Jun, JNK2 can become predominantly nuclear (143). Such piggyback transport on partner proteins can be independent of activation state and would allow them to form a dynamic equilibrium between the nucleus and the cytoplasm even in the absence of JNK pathway activation.…”

Section: Jnk Nucleo-cytoplasmic Traffickingmentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

387

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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“…The abundance of them in the nucleus correlates with their activity on the target (25).To define the location of phosphorylated c-Jun, Fra-1, and ATF-2, immunofluorescent images were compared between groups with or without UTP stimulation for 30 min. In control groups without stimulation, very little FITC signal was detected for any of the three phosphorylated subunits.…”

Section: P2y2r Activation Boosts Tf Expression By Promoting Genementioning

confidence: 99%

Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells

Liu

Zhang

Wang

et al. 2016

Journal of Biological Chemistry

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We recently reported that the P2Y2 receptor (P2Y2R) is the predominant nucleotide receptor expressed in human coronary artery endothelial cells (HCAEC) and that P2Y2R activation by ATP or UTP induces dramatic up-regulation of tissue factor (TF), a key initiator of the coagulation cascade. However, the molecular mechanism of this P2Y2R-TF axis remains unclear. Here, we report the role of a newly identified AP-1 consensus sequence in the TF gene promoter and its original binding components in P2Y2R regulation of TF transcription. Using bioinformatics tools, we found that a novel AP-1 site at ؊1363 bp of the human TF promoter region is highly conserved across multiple species. Activation of P2Y2R increased TF promoter activity and mRNA expression in HCAEC. Truncation, deletion, and mutation of this distal AP-1 site all significantly suppressed TF promoter activity in response to P2Y2R activation. EMSA and ChIP assays further confirmed that upon P2Y2R activation, c-Jun, ATF-2, and Fra-1, but not the typical c-Fos, bound to the new AP-1 site. In addition, loss-of-function studies using siRNAs confirmed a positive transactivation role of c-Jun and ATF-2 but unexpectedly revealed a strong negative role of Fra-1 in P2Y2R-induced TF up-regulation. Furthermore, we found that P2Y2R activation promoted ERK1/2 phosphorylation through Src, leading to Fra-1 activation, whereas Rho/JNK mediated P2Y2R-induced activation of c-Jun and ATF-2. These findings reveal the molecular basis for P2Y G protein-coupled receptor control of endothelial TF expression and indicate that targeting the P2Y2R-Fra-1-TF pathway may be an attractive new strategy for controlling vascular inflammation and thrombogenicity associated with endothelial dysfunction.Nucleotides matter more than being the universal currency of energy transaction and the building blocks of genes. They are also short term signaling molecules and long term trophic factors through P2X or P2Y receptors (1). Among the eight G protein-coupled P2Y nucleotide receptors, the ADP-preferring

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c-Jun localizes to the nucleus independent of its phosphorylation by and interaction with JNK and vice versa promotes nuclear accumulation of JNK

Cited by 36 publications

References 17 publications

Increased expression of c-Jun in nonalcoholic fatty liver disease

Increased expression of c-Jun in nonalcoholic fatty liver disease

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Purinergic P2Y2 Receptor Control of Tissue Factor Transcription in Human Coronary Artery Endothelial Cells

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