UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arabidopsis thaliana De-etiolated-1 (AtDET1) is a highly conserved protein, with orthologs in vertebrate and invertebrate organisms. AtDET1 negatively regulates photomorphogenesis, but its biochemical mechanism and function in other species are unknown. We report that human DET1 (hDET1) promotes ubiquitination and degradation of the proto-oncogenic transcription factor c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1. Ablation of any subunit by RNA interference stabilized c-Jun and increased c-Jun-activated transcription. These findings characterize a c-Jun ubiquitin ligase and define a specific function for hDET1 in mammalian cells.
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PMID:Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. 1473 64

In this study, we report that the PEA3 group members interact with the mammalian really interesting new gene (RING) E3 ubiquitin ligase constitutive photomorphogenetic 1 (COP1), which mediates ubiquitylation and subsequent proteasome degradation of the p53 and c-Jun transcription factors. This interaction is mediated by the central region of COP1 including the coiled-coil domain and two COP1-interacting consensus motifs localized in the well-conserved N-terminal transactivation domain of the PEA3 group members. At the transcriptional level, COP1 reduces the transcriptional activity of ERM and the two other PEA3 group proteins on Ets-responsive reporter genes; this effect being dependent on the RING domain of COP1 and the two COP1-interacting motifs of ERM. Reduced transcriptional activity was, however, not related to COP1-induced changes in ERM stability. In fact, increased ubiquitylation and subsequent proteasome-mediated degradation of ERM is achieved only when COP1 is expressed with DET1, a key COP1 partner within the ubiquitylation complex. Conversely, we show that the depletion of COP1 or DET1 by small interference RNA (siRNA) in U2OS cells stabilizes endogenous ERM whereas only COP1 knockdown enhances expression of ICAM-1, a gene regulated by this transcription factor. These results indicate that COP1 is a complex regulator of ERM and the two other PEA3 group members.
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PMID:The E3 ubiquitin ligase complex component COP1 regulates PEA3 group member stability and transcriptional activity. 2006 82

DET1 (De-etiolated 1) is a chromatin binding protein involved in developmental regulation in both plants and animals. DET1 is largely restricted to multicellular eukaryotes, and here we report the characterization of a DET1 homolog from the social amoeba Dictyostelium discoideum. As in other species, Dictyostelium DET1 is nuclear localized. In contrast to other species, where it is an essential protein, loss of DET1 is nonlethal in Dictyostelium, although viability is significantly reduced. The phenotype of the det1(-) mutant is highly pleiotropic and results in a large degree of heterogeneity in developmental parameters. Loss of DET1 results in delayed and abnormal development with enlarged aggregation territories. Mutant slugs displayed cell type patterning with a bias toward the prestalk pathway. A number of DET1-interacting proteins are conserved in Dictyostelium, and the apparently conserved role of DET1 in regulatory pathways involving the bZIP transcription factors DimB, c-Jun, and HY5 suggests a highly conserved mechanism regulating development in multicellular eukaryotes. While the mechanism by which DET1 functions is unclear, it appears that it has a key role in regulation of developmental plasticity and integration of information on environmental conditions into the developmental program of an organism.
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PMID:Characterization of the Dictyostelium homolog of chromatin binding protein DET1 suggests a conserved pathway regulating cell type specification and developmental plasticity. 2119 47

The intracellular parasite Theileria is the only eukaryote known to transform its mammalian host cells. We investigated the host mechanisms involved in parasite-induced transformation phenotypes. Tumour progression is a multistep process, yet 'oncogene addiction' implies that cancer cell growth and survival can be impaired by inactivating a single gene, offering a rationale for targeted molecular therapies. Furthermore, feedback loops often act as key regulatory hubs in tumorigenesis. We searched for microRNAs involved in addiction to regulatory loops in leukocytes infected with Theileria parasites. We show that Theileria transformation involves induction of the host bovine oncomiR miR-155, via the c-Jun transcription factor and AP-1 activity. We identified a novel miR-155 target, DET1, an evolutionarily-conserved factor involved in c-Jun ubiquitination. We show that miR-155 expression led to repression of DET1 protein, causing stabilization of c-Jun and driving the promoter activity of the BIC transcript containing miR-155. This positive feedback loop is critical to maintain the growth and survival of Theileria-infected leukocytes; transformation is reversed by inhibiting AP-1 activity or miR-155 expression. This is the first demonstration that Theileria parasites induce the expression of host non-coding RNAs and highlights the importance of a novel feedback loop in maintaining the proliferative phenotypes induced upon parasite infection. Hence, parasite infection drives epigenetic rewiring of the regulatory circuitry of host leukocytes, placing miR-155 at the crossroads between infection, regulatory circuits and transformation.
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PMID:OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes. 2363 92

Infiltrating neutrophils are known to promote in the development of tumor. However, it is unclear whether and how neutrophils are involved in triggering the growth of dormant metastases. Here we show that 14,15-epoxyeicosatrienoic acid (14,15-EET) can trigger the growth of dormant micrometastases by inducing neutrophilic infiltration and converting neutrophil function. 14,15-EET triggered neutrophil infiltration in metastatic lesions by activating STAT3 and JNK pathways to induce the expression of human IL-8 and murine CXCL15 in corresponding tumor cells. The continuous expression of hIL-8/mCXCL15 was maintained by the sustained and enhanced activation of JNK pathway. 14,15-EET up-regulated miR-155 expression by activating STAT3 and JNK pathways. miR-155 in turn down-regulated the expression of SHIP1 and DET1, thus augmenting the activation of JNK and c-Jun. Moreover, the function of neutrophils was converted from tumor-suppressing to tumor-promoting by 14,15-EET in vivo. By inducing the production of G-CSF/IL-6 in vivo, 14,15-EET induced the enhancement of STAT3 activation in neutrophils to increase MMP-9 expression and decrease TRAIL expression. Neutrophil-derived MMP-9 was required for 14,15-EET to induce angiogenesis during the growth of dormant micrometastases. Depleting neutrophils or inhibiting hIL-8/mCXCL15 up-regulation resulted in the failure of 14,15-EET to promote the development of micrometastases. These findings reveal a mechanism through which the infiltration and tumor-promoting function of neutrophils could be induced to trigger the growth of dormant metastases, which might be a driving force for the tumor recurrence based on dormant metastases.
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PMID:14,15-EET induces the infiltration and tumor-promoting function of neutrophils to trigger the growth of minimal dormant metastases. 2727 Mar 16

The E3 ubiquitin ligase CRL4^COP1/DET1 is active in the absence of ERK signaling, modifying the transcription factors ETV1, ETV4, ETV5, and c-JUN with polyubiquitin that targets them for proteasomal degradation. Here we show that this posttranslational regulatory mechanism is active in neurons, with ETV5 and c-JUN accumulating within minutes of ERK activation. Mice with constitutive photomorphogenesis 1 (Cop1) deleted in neural stem cells showed abnormally elevated expression of ETV1, ETV4, ETV5, and c-JUN in the developing brain and spinal cord. Expression of c-JUN target genes Vimentin and Gfap was increased, whereas ETV5 and c-JUN both contributed to an expanded number of cells expressing genes associated with gliogenesis, including Olig1, Olig2, and Sox10. The mice had subtle morphological abnormalities in the cerebral cortex, hippocampus, and cerebellum by embryonic day 18 and died soon after birth. Elevated c-JUN, ETV5, and ETV1 contributed to the perinatal lethality, as several Cop1-deficient mice also lacking c-Jun and Etv5, or lacking Etv5 and heterozygous for Etv1, were viable.
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PMID:Ubiquitin ligase COP1 coordinates transcriptional programs that control cell type specification in the developing mouse brain. 3032 23

Periodontitis is a bacteria-driven inflammatory destructive disease that leads to attachment loss, bone resorption, and even tooth loss. Accumulating studies revealed that macrophages might play an nonnegligible role during the processes of periodontitis. However, the underlying mechanism remains largely unknown. In this study, we found novel Akt2/JNK1/2/c-Jun and Akt2/miR-155-5p/DET1/c-Jun signaling pathways that regulated the polarization of macrophages and altered periodontal inflammatory status. Through hematoxylin and eosin, immunostaining, and immunofluorescence staining of clinical specimens, a higher number of M1 phenotype macrophage infiltration was found in periodontitis than in normal controls. Flow cytometry and immunofluorescence showed that overexpression of Akt2 in RAW 264.7 cells induced M1 macrophage polarization and decreased M2 polarization, while knockdown of Akt2 exerted an opposite effect. Furthermore, overexpression of Akt2 activated the JNK pathway and then increased the release of proinflammatory mediators, while knockdown of Akt2 downregulated the above genes accordingly. Importantly, the macrophage polarization and the subsequent alteration of pathway molecules induced by overexpression of Akt2 could be rescued by Akt2 and JNK inhibitors. Moreover, JNK inhibition could facilitate M2 polarization of macrophages. In a mouse periodontitis model, the novel signaling pathway as well as clinical phenotype was further verified. Inhibition of Akt2 facilitated macrophage M2 polarization and rescued the bone loss due to periodontitis. Collectively, we identified novel Akt2/JNK1/2/c-Jun and Akt2/miR-155-5p/DET1/c-Jun signaling pathways that regulate macrophage polarization and highlight that Akt2 inhibition promotes M2 polarization of macrophages and can be a novel potential candidate in the treatment of periodontitis.
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PMID:Akt2 Affects Periodontal Inflammation via Altering the M1/M2 Ratio. 3222 53