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)

Functional analysis of polycystin-1, the product of the gene most frequently mutated in autosomal dominant polycystic kidney disease, has revealed that this protein is involved in the regulation of diverse signaling pathways such as the activation of the transcription factor AP-1 and modulation of Wnt signaling. However, the initial steps involved in the activation of such cascades have remained unclear. We demonstrated previously that the C-terminal cytosolic tail of polycystin-1 binds and activates heterotrimeric G proteins in vitro. To test if polycystin-1 can activate cellular signaling cascades via heterotrimeric G protein subunits, polycystin-1 C-terminal tail-mediated c-Jun N-terminal kinase (JNK) and AP-1 activities were assayed in transiently transfected 293T cells in the presence of dominant-negative, G protein inhibiting constructs, and in the presence of cotransfected Galpha subunits. The results showed that polycystin-1-mediated JNK/AP-1 activation is mediated by Galpha and Gbetagamma subunits. Polycystin-1-mediated AP-1 activity could be significantly augmented by cotransfected Galpha(i), Galpha(q), and Galpha(12/13) subunits, suggesting that polycystin-1 can couple with and activate several heterotrimeric G protein families.
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PMID:Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins. 1191 16

Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, beta-catenin and T-cell factor/lymphoid-enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.
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PMID:Aberrant polycystin-1 expression results in modification of activator protein-1 activity, whereas Wnt signaling remains unaffected. 1508 66

Recently, evidence is accumulating pointing to a function of the COP9 signalosome (CSN) in regulation of ubiquitination by specific ubiquitin ligases. Here, we demonstrate by mammalian two-hybrid analysis that the transcriptional regulators and substrates of the ubiquitin system Id1 and Id3, but not Id2 and Id4, bind to the CSN subunit CSN5. Pull-down experiments revealed that Id3 physically interacts with the CSN complex. Additional far Western and pull-down studies with Id3 support our two-hybrid data and show that the transcription regulator can bind to CSN5 and CSN7. Recombinant Id3 is not phosphorylated by the CSN-associated kinases CK2 and PKD. However, it inhibits c-Jun and CSN2 phosphorylation by the isolated CSN complex and by the recombinant CK2. The inhibitors of CSN associated kinases, curcumin and emodin, significantly induce ubiquitination and proteasome-dependent degradation of transiently expressed Id3 in HeLa cells. Proteasome-dependent degradation of endogenous Id1 in HeLa cells is also stimulated by treatment with curcumin or emodin. Ubiquitination of Id3 is shown directly by cotransfection of HeLa cells with Id3 and His-ubiquitin cDNA. Curcumin increased Id3-ubiquitin conjugate formation, as shown by Western blotting and His-pull-downs. In addition, overexpression of CSN2 leads to stabilization of Id3 protein. On the basis of these data, it is speculated that CSN-mediated phosphorylation inhibits ubiquitination of Id1 and Id3.
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PMID:Ubiquitin-dependent degradation of Id1 and Id3 is mediated by the COP9 signalosome. 1545 66

Autosomal dominant polycystic kidney disease is a common inherited disorder that predominantly manifests with the formation of fluid-filled cysts in both kidneys. The disease can be accounted for by a mutation in either the PKD1 or the PKD2 gene. It was demonstrated previously that aberrant expression of the PKD1 gene product, polycystin-1, results in modification of activator protein-1 (AP-1) transcription factor activity in cultured renal epithelial cells. Here, it is reported that activity of the AP-1 components c-Jun, ATF2, and c-Fos is altered in renal cystic tissue of patients with autosomal dominant polycystic kidney disease and of hypomorphic Pkd1 mice with polycystic kidney disease. Data were obtained using immunohistochemical and Western blot analysis. Significant upregulation of Thr71- and Thr69/71-phosphorylated ATF2 and Ser73-phosphorylated c-Jun and increased c-Fos were detected in small cysts and (dilated) ducts and tubules surrounded by fibrotic interstitium. The data indicate that various AP-1 components are constitutively activated in polycystic kidney disease and suggest that aberrant AP-1 activity is relevant for cyst formation.
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PMID:Increased activity of activator protein-1 transcription factor components ATF2, c-Jun, and c-Fos in human and mouse autosomal dominant polycystic kidney disease. 1604 73

Inhalation of asbestos and oxidant-generating pollutants causes injury and compensatory proliferation of lung epithelium, but the signaling mechanisms that lead to these responses are unclear. We hypothesized that a protein kinase (PK)Cdelta-dependent PKD pathway was able to regulate downstream mitogen-activated protein kinases, affecting pro- and anti-apoptotic responses to asbestos. Elevated levels of phosphorylated PKD (p-PKD) were observed in distal bronchiolar epithelial cells of mice inhaling asbestos. In contrast, PKCdelta-/- mice showed significantly lower levels of p-PKD in lung homogenates and in situ after asbestos inhalation. In a murine lung epithelial cell line, asbestos caused significant increases in the phosphorylation of PKCdelta-dependent PKD, ERK1/2, and JNK1/2/c-Jun that occurred with decreases in the BH3-only pro-apoptotic protein, Bim. Silencing of PKCdelta, PKD, and use of small molecule inhibitors linked the ERK1/2 pathway to the prevention of Bim-associated apoptosis as well as the JNK1/2/c-Jun pathway to the induction of apoptosis. Our studies are the first to show that asbestos induces PKD phosphorylation in lung epithelial cells both in vivo and in vitro. PKCdelta-dependent PKD phosphorylation by asbestos is causally linked to a cellular pathway that involves the phosphorylation of both ERK1/2 and JNK1/2, which play opposing roles in the apoptotic response induced by asbestos.
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PMID:A protein kinase Cdelta-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and Bim-associated apoptosis by asbestos. 1911 64