Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.
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PMID:Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine. 1971 31

Wnt/beta-catenin canonical pathway is critical for normal embryonic development; mutations and aberrant expression of specific components of this pathway can be oncogenic. Mitogen-activated protein kinase (MAPK) pathways, prominent in intracellular signaling, have been shown to have unique and provocative roles that impact the Wnt/beta-catenin signaling. We discuss recent insights that implicate the three major pathways of the MAPK network, i.e., mediated by p38, c-Jun N-terminal (JNK) kinase and Extra-cellular-Regulated Kinases (ERK) and their downstream signaling elements in Wnt/beta-catenin signaling. Novel "crosstalk" among MAPK and Wnt/beta-catenin canonical signaling pathways is essential. A fuller understanding of how such signaling is integrated during development is a high-value target for future research.
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PMID:Mitogen-activated protein kinases and Wnt/beta-catenin signaling: Molecular conversations among signaling pathways. 1951 64

Wnt signalling is a crucial signalling pathway controlling intestinal homeostasis and cancer. We show here that the JNK MAP kinase pathway and one of its most important substrates, the AP-1 transcription factor c-Jun, modulates Wnt signalling strength in the intestine. Transgenic gut-specific augmentation of JNK signalling stimulated progenitor cell proliferation and migration, resulting in increased villus length. In the crypt, c-Jun protein was highly expressed in progenitor cells and the absence of c-Jun resulted in decreased proliferation and villus length. In addition to several known c-Jun/AP-1 target genes, expression of Wnt target genes Axin2 and Lgr5 were stimulated by JNK activation, suggesting a cross talk of JNK to Wnt signalling. Expression of the Wnt pathway component TCF4 was controlled by JNK activity, and chromatin immunoprecipitation and reporter assays identified tcf4 as a direct c-Jun target gene. Consequently, increased JNK activity accelerated tumourigenesis in a model of colorectal carcinogenesis. As c-jun is a direct target of the TCF4/beta-catenin complex, the control of tcf4 expression by JNK/c-Jun leads to a positive feedback loop that connects JNK and Wnt signalling. This mechanism regulates the physiological function of progenitor cells and oncogenic transformation.
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PMID:JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. 1952 38

The c-Jun amino-terminal kinase (JNK) is an important player in inflammation, proliferation, and apoptosis. More recently, JNK was found to regulate cell migration by phosphorylating paxillin. Here, we report a novel role of JNK in cell adhesion. Specifically, we provide evidence that JNK binds to E-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by GSK-3beta. Inhibition of JNK kinase activity using dominant-negative constructs reduces phosphorylation of beta-catenin and promotes localization of E-cadherin/beta-catenin complex to cell-cell contact sites. Conversely, activation of JNK induces beta-catenin phosphorylation and disruption of cell contacts, which are prevented by JNK siRNA. We propose that JNK binds to beta-catenin and regulates formation of adherens junctions, ultimately controlling cell-to-cell adhesion.
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PMID:JNK phosphorylates beta-catenin and regulates adherens junctions. 1966 22

Interactions between transcription and signaling are fundamentally important for understanding both the structure and function of genetic pathways and their role in diseases such as cancer. The finding that beta-catenin/TCF4 and JNK/c-Jun cooperate has important implications in carcinogenesis. Previously, we found that binding of c-Jun and beta-catenin/TCF4 to the c-jun promoter is dependent upon JNK activity, thus one role for this complex is to contribute to the repression and/or activation of genes that may mediate cell maintenance, proliferation, differentiation, and death, whereas deregulation of these signals may contribute to carcinogenesis. Here we address the functional links reported between activated beta-catenin/JNK signaling pathways, their component genes, and their common targets, and discuss how alterations in the properties of these genes lead to the development of cancer.
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PMID:The links between transcription, beta-catenin/JNK signaling, and carcinogenesis. 1967 87

It has been demonstrated that ubiquitin-conjugated proteins were accumulated by ectopically-expressed S5a as well as the ubiquitin-interacting motifs of S5a (S5a-UIMs). In this study, we further found that free S5a-UIMs stabilized only a subset of proteasomal substrates including p53, c-Fos, c-Jun, and p27 but not beta-catenin, p15, and ornithine decarboxylase. Both S5a-UIMs and epoxomicin inhibited the proliferation of A549 lung cancer cells but arrest at the different stages of cell cycle. Together, our results suggest a potential role of S5a-UIMs as an upstream proteasomal inhibitor by blocking the subset of substrates from delivery to the 26S proteasome.
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PMID:The ubiquitin-interacting motifs of S5a as a unique upstream inhibitor of the 26S proteasome. 1969 30

Efficient transcription depends upon efficient physical and functional interactions between transcriptosome complexes and DNA. We have previously shown that IL-1beta-induced lymphoid enhancer binding factor 1 (Lef1) regulates the transcription of its target genes COX2 and MMP13 in mouse chondrocytes by binding to the Lef1 binding sites located in the 3' region. In this study, we investigated how the 3' region-bound Lef1 regulates expression of target genes. IL-1beta stimulation induced gene looping in COX2 and MMP13 genomic loci, which is mediated by the physical interaction of Lef1 with its binding partners, including beta-catenin, AP-1, and NF-kappaB. As shown by chromosome conformation capture (3C) assay, the 5' and 3' genomic regions of these genes were juxtaposed in an IL-1beta-stimulation dependent manner. Lef1 played a pivotal role in this gene looping; Lef1 knockdown decreased the incidence of gene looping, while Lef1 overexpression induced it. Physical interactions between the 3' region-bound Lef1 and promoter-bound transcription factors AP-1 or NF-kappaB in COX2 and MMP13, respectively, were increased upon stimulation, leading to synergistic up-regulation of gene expression. Knockdown of RelA or c-Jun decreased the formation of gene loop and down-regulated cyclooxygenase 2 (COX2) or matrix metalloproteinase 13 (MMP13) transcription levels. However, overexpression of RelA or c-Jun along with Lef1 increased the looping and their expression levels. Our results indicate a novel function of Lef1, as a mediator of gene looping between 5' and 3' regions. Gene looping may serve to delineate the transcription unit in the inducible gene transcription of mammalian cells.
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PMID:Lymphoid enhancer binding factor 1 regulates transcription through gene looping. 1978 77

The signaling mechanisms facilitating cardiomyocyte (CM) differentiation from bone marrow (BM)-derived mesenchymal stem cells (MSCs) are not well understood. 5-Azacytidine (5-Aza), a DNA demethylating agent, induces expression of cardiac-specific genes, such as Nkx2.5 and alpha-MHC, in mouse BM-derived MSCs. 5-Aza treatment caused significant up-regulation of glycogen synthase kinase (GSK)-3beta and down-regulation of beta-catenin, whereas it stimulated GSK-3alpha expression only modestly. The promoter region of GSK-3beta was heavily methylated in control MSCs, but was demethylated by 5-Aza. Although overexpression of GSK-3beta potently induced CM differentiation, that of GSK-3alpha induced markers of neuronal and chondrocyte differentiation. GSK-3 inhibitors, including LiCl, SB 216743, and BIO, abolished 5-Aza-induced up-regulation of CM-specific genes, suggesting that GSK-3 is necessary and sufficient for CM differentiation in MSCs. Although specific knockdown of endogenous GSK-3beta abolished 5-Aza-induced expression of cardiac specific genes, surprisingly, that of GSK-3alpha facilitated CM differentiation in MSCs. Although GSK-3beta is found in both the cytosol and nucleus in MSCs, GSK-3alpha is localized primarily in the nucleus. Nuclear-specific overexpression of GSK-3beta failed to stimulate CM differentiation. Down-regulation of beta-catenin mediates GSK-3beta-induced CM differentiation in MSCs, whereas up-regulation of c-Jun plays an important role in mediating CM differentiation induced by GSK-3alpha knockdown. These results suggest that GSK-3alpha and GSK-3beta have distinct roles in regulating CM differentiation in BM-derived MSCs. GSK-3beta in the cytosol induces CM differentiation of MSCs through down-regulation of beta-catenin. In contrast, GSK-3alpha in the nucleus inhibits CM differentiation through down-regulation of c-Jun.
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PMID:Distinct roles of glycogen synthase kinase (GSK)-3alpha and GSK-3beta in mediating cardiomyocyte differentiation in murine bone marrow-derived mesenchymal stem cells. 1985 10

Wnt/beta-catenin signaling mediates renal fibrosis in several model systems including diabetic nephropathy. Dickkopf-1 (DKK-1) is an endogenous inhibitor of Wnt/beta-catenin signaling, but whether DKK-1 modulates diabetic nephropathy is unknown. Here, we studied whether DKK-1 participates in high glucose (HG)-induced expression of profibrotic factors and renal damage. In vitro, HG increased expression of DKK1, receptor Kremen-2, TGF-beta1, and fibronectin in mesangial cells. Loss and gain of DKK1 function modulated HG-mediated c-Jun, TGF-beta1, and fibronectin expression. DKK1 mediated HG-induced phosphorylation of Ser45-beta-catenin and reduction of nuclear beta-catenin levels, but not phosphorylation of ERK kinase. Wnt3a protein and the beta-catenin (Delta45) mutation increased nuclear beta-catenin but abrogated HG-induced DKK1 and fibronectin expression. Exogenous DKK1 antisense oligonucleotide attenuated the increase in both serum DKK1 and urinary protein excretion in streptozotocin-induced diabetic rats. Knocking down DKK1 inhibited mesangial expression of TGF-beta1 and fibronectin and reduced both the glomerular volume and deposition of mesangial matrix in diabetic kidneys. Taken together, DKK1 mediates HG-induced destabilization of beta-catenin and matrix accumulation in mesangial cells. Knocking down DKK1 prevents diabetes-induced renal dysfunction and microstructure deterioration, suggesting that inhibition of DKK1offers therapeutic potential for diabetic nephropathy.
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PMID:Dickkopf-1 promotes hyperglycemia-induced accumulation of mesangial matrix and renal dysfunction. 2001 66

A central point of regulation in the Wnt/beta-catenin signalling pathway is the formation of the beta-catenin destruction complex. Axin1, an essential negative regulator of Wnt signalling, serves as a scaffold within this complex and is critical for rapid turnover of beta-catenin. To examine the mechanism by which Wnt signalling disables the destruction complex, we used an immunoprecipitation-coupled proteomics approach to identify novel endogenous binding partners of Axin1. We found mitogen-activated protein kinase kinase kinase 1 (MAP3K1) as an Axin1 interactor in Ls174T colorectal cancer (CRC) cells. Importantly, confirmation of this interaction in HEK293T cells indicated that the Axin1-MAP3K1 interaction is induced and modulated by Wnt stimulation. siRNA depletion of MAP3K1 specifically abrogated TCF/LEF-driven transcription and Wnt3A-driven endogenous gene expression in both HEK293T as well as DLD-1 CRC. Expression of ubiquitin ligase mutants of MAP3K1 abrogated TCF/LEF transcription, whereas kinase mutants had no effect in TCF-driven activity, highlighting the essential role of the MAP3K1 E3 ubiquitin ligase activity in regulation of the Wnt/beta-catenin pathway. These results suggest that MAP3K1, previously reported as an Axin1 inter-actor in c-Jun NH(2)-terminal kinase pathway, is also involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes.
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PMID:MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway. 2012 90


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