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)

Members of the helix-loop-helix (HLH) family of proteins bind DNA and activate transcription as homo- and heterodimers. Myogenin is a muscle-specific HLH protein that binds DNA in vitro as a heterodimer with several widely expressed HLH proteins, such as the E2A gene products E12 and E47. We describe a method for detection of protein-protein interactions among HLH proteins in vivo in which dimerization through the HLH motif reconstructs a hybrid transcription factor containing the DNA-binding domain of yeast GAL4 linked to one HLH motif and the activation domain of VP-16 linked to another. We have used this assay to investiagate whether myogenin forms homomeric or heteromeric complexes in vivo and to determine whether growth factors and oncogenes that inhibit myogenesis influence myogenin's ability to dimerize. The results show that myogenin heterodimerizes with E12 and E47 in vivo, but it does not homodimerize to a measurable extent. Peptide growth factors, as well as the immediate early gene products c-Jun, v-Fos, and c-Myc, inhibit the activity of myogenin through a mechanism independent of its association with E2A products.
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PMID:Analysis of the oligomerization of myogenin and E2A products in vivo using a two-hybrid assay system. 132 37

Pancreatic beta-cell-type-specific transcription of the insulin gene is principally controlled by trans-acting factors which influence insulin control element (ICE)-mediated expression. The ICE activator is composed, in part, of the basic helix-loop-helix proteins E12, E47, and E2-5 encoded by the E2A gene. Previous experiments showed that ICE activation in beta cells was repressed in vivo by the c-jun proto-oncogene (E. Henderson and R. Stein, Mol. Cell. Biol. 14:655-662, 1994). Here we focus on the mechanism by which c-Jun inhibits ICE-mediated activation. c-Jun was shown to specifically repress the transactivation potential of the E2A proteins. Thus, we found that the activity of GAL4:E2A fusion constructs was inhibited by c-Jun. The transrepression capabilities of c-Jun were detected only in pancreatic islet cell lines that contained a functional ICE activator. Repression of GAL4:E2A was mediated by the basic leucine zipper regions of c-Jun, which are also the essential regions of this protein necessary for controlling ICE activator-stimulated expression in vivo. The specific target of c-Jun repression was the transactivation domain (located between amino acids 345 and 408 in E12 and E47) conserved in E12, E47, and E2-5. In contrast, the activation domain unique to the E12 and E47 proteins (located between amino acids 1 and 99) was unresponsive to c-Jun. Our results indicate that c-Jun inhibits insulin gene transcription in beta cells by reducing the transactivation potential of the E2A proteins present in the ICE activator complex.
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PMID:c-jun inhibits insulin control element-mediated transcription by affecting the transactivation potential of the E2A gene products. 786 33

Studies are described that allow for the in vivo detection of helix-loop-helix (HLH) protein-protein interaction. The assay used requires HLH protein-protein interaction to reconstitute a functional GAL4 transcriptional activator, which in turn activates a reporter gene placed downstream of GAL4 DNA binding sequences. Using this assay, we are able to detect intracellular heterodimerization but not homodimerization of the MyoD, E12, and Id gene products. In addition, using this system we are unable to detect stable heterodimerization between MyoD and c-Jun. We also show that expression of activated rasH gene product does not inhibit and may stabilize HLH protein-protein interaction. This system may be of general utility in studying the modulation of transcription factor interactions.
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PMID:Detection and modulation in vivo of helix-loop-helix protein-protein interactions. 838 Jan 66

Although a number of studies have implicated c-Jun in neuronal death and axonal regeneration, it is unknown whether Jun function is essential for either response. One approach to resolve this issue is to analyze knock-out mice. However, c-jun-null mice die at midgestation, precluding critical investigation. Therefore, a xenograft paradigm was used in which retinas from embryonic day 12.5 (E12.5) c-jun nullizygous or wild-type mice were transplanted onto the superior colliculus of newborn rats. The rats were allowed to develop, and the grafts were assayed at various times for cell death and axon growth. Histologically, grafts of both genotypes developed in identical manners and had morphological characteristics of retinas. A functional c-jun allele was not essential for axogenesis, because ganglion cells in retinal grafts from c-jun nullizygous mice developed axons that projected into the colliculus. Programmed cell death (PCD) was also evident in the age-appropriate regions of the retina in both wild-type and c-jun-null grafts. Furthermore, there were no discernible differences in the number or location of dying cells in the two genotypes. That c-jun was not essential for PCD was supported by two additional findings. First, a c-jun-lacZ reporter gene was expressed in many cells in developing and grafted retinas, although only a few of these cells were destined to die. Second, in E12.5 c-jun-null embryos there were normal levels of PCD in the trigeminal ganglion. Together, these data indicate that c-Jun is not essential for axon growth in the retina or for PCD in the retina and trigeminal ganglion.
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PMID:c-jun Is dispensable for developmental cell death and axogenesis in the retina. 1034 Dec 38

Mice lacking the stress-signaling kinase SEK1 die from embryonic day 10.5 (E10.5) to E12.5. Although a defect in liver formation is accompanied with the embryonic lethality of sek1(-/-) mice, the mechanism of the liver defect has remained unknown. In the present study, we first produced a monoclonal antibody specifically recognizing murine hepatoblasts for the analysis of liver development and further investigated genetic interaction ofsek1 with tumor necrosis factor-alpha receptor 1 gene (tnfr1) and protooncogene c-jun, which are also responsible for liver formation and cell apoptosis. The defective liver formation in sek1(-/-) embryos was not protected by additionaltnfr1 mutation, which rescues the embryonic lethality of mice lacking NF-kappaB signaling components. There was a progressive increase in the hepatoblast cell numbers of wild-type embryos from E10.5 to E12.5. Instead, impaired hepatoblast proliferation was observed in sek1(-/-) livers from E10.5, though fetal liver-specific gene expression was normal. The impaired phenotype in sek1(-/-) livers was more severe than in c-jun(-/-) embryos, and sek1(-/-) c-jun(-/-) embryos died more rapidly before E8.5. The hepatoblast proliferation required no hematopoiesis, since liver development was not impaired in AML1(-/-) mice that lack hematopoietic functions. Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek1(-/-) livers. Thus, SEK1 appears to play a crucial role in hepatoblast proliferation and survival in a manner apparently different from NF-kappaB or c-Jun.
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PMID:SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti-apoptosis. 1237 7

Recognition of mother's voice by human neonates and behavioral responses of birds and animals to sounds experienced prenatally emphasize the role of sensory inputs in auditory system development. Spontaneous and experience driven neural activity influence the neural circuits' refinement in developing brain. However, cellular mechanisms endowing plasticity for such structural refinement during critical developmental periods are less understood. Sensory stimulation induces fluctuating expression of transcription factors (TFs) of Fos, Jun, and Krox families in the related brain nuclei to activate genes to synthesize proteins such as those needed for cytoskeletal structures, ion channels, and regeneration. To understand the cellular mechanism of response to prenatal auditory stimulation, we studied the expression of c-Fos and c-Jun in brainstem auditory nuclei, nucleus magnocellularis, and nucleus laminaris of the domestic chick. The chick brainstems, five each of E8 (embryonic day 8), E12, E16, E20, and posthatch day 1 were processed for immunohistochemistry as well as Western blotting and quantified using image analysis systems. In controls, c-Fos and c-Jun expression in both the nuclei was developmentally up-regulated. Reduced c-Fos expression and increase in c-Jun was temporarily observed between E12-16. In the stimulated groups, c-Fos expression was elevated while c-Jun showed a reduction matched to controls. This diametrically opposing pattern of c-Fos and c-Jun expression in response to stimulation is indicative of cell survival. Thus the expression of TFs in the auditory nuclei shows a relationship beyond a simple stimulation-activity-expression. While developmental signals control the expression of TFs, extra sensory stimulation modulates their expression to possibly support neuronal survival and enhance synthesis of other proteins.
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PMID:Developmentally regulated expression of c-Fos and c-Jun in the brainstem auditory nuclei of Gallus domesticus is modified by prenatal auditory enrichment. 1538 80

c-Jun is a transcription factor that is involved in various cellular events, including apoptotic cell death. For example, phosphorylation of c-Jun is one of the earliest biochemical changes detected in dying sympathetic neurons after NGF deprivation in vitro. However, currently, it is not known whether a similar molecular event is involved in the developmental programmed cell death (PCD) of neurons in vivo. We observed that only a subpopulation of motoneurons (MNs) exhibit c-Jun phosphorylation during the PCD period in chick [embryonic day 5 (E5)-E12] and mouse (E13-E18) embryos. Experimental perturbation of MN survival-promoting signals by limb bud removal (reduced signals) or by activity blockade (increased signals) in the chick embryo demonstrated that the presence of those signals is negatively correlated with the number of c-Jun-phosphorylated MNs. This suggests that insufficient survival signals (e.g., neurotrophic factors) may induce c-Jun phosphorylation of MNs in vivo. Consistent with the idea that c-Jun phosphorylation is a reversible event during normal PCD of MNs, we found that c-Jun phosphorylation was transiently observed in a subpopulation of mouse MNs rescued from PCD by deletion of the proapoptotic gene Bax. Inhibition of c-Jun signaling significantly reduced MN death in chick embryo, indicating that activation of c-Jun signaling is necessary for the PCD of MNs. Together, c-Jun phosphorylation appears to be required for the initiation of an early and reversible event in the intracellular PCD cascade in vivo after loss of survival-promoting signals such as neurotrophic factors.
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PMID:Phosphorylation of c-Jun in avian and mammalian motoneurons in vivo during programmed cell death: an early reversible event in the apoptotic cascade. 1594 87

Large numbers of neurons are eliminated by apoptosis during nervous system development. For instance, in the mouse dorsal root ganglion (DRG), the highest incidence of cell death occurs between embryonic days 12 and 14 (E12-E14). While the cause of cell death and its biological significance in the nervous system is not entirely understood, it is generally believed that limiting quantities of neurotrophins are responsible for neuronal death. Between E12 and E14, developing DRG neurons pass through tissues expressing high levels of axonal guidance molecules such as Semaphorin 3A (Sema3A) while navigating to their targets. Here, we demonstrate that Sema3A acts as a death-inducing molecule in neurotrophin-3 (NT-3)-, brain-derived neurotrophic factor (BDNF)- and nerve growth factor (NGF)-dependent E12 and E13 cultured DRG neurons. We show that Sema3A most probably induces cell death through activation of the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway, and that this cell death is blocked by a moderate increase in NGF concentration. Interestingly, increasing concentrations of other neurotrophic factors, such as NT-3 or BDNF, do not elicit similar effects. Our data suggest that the number of DRG neurons is determined by a fine balance between neurotrophins and Semaphorin 3A, and not only by neurotrophin levels.
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PMID:Semaphorin 3A and neurotrophins: a balance between apoptosis and survival signaling in embryonic DRG neurons. 1633 28

The Smad2/3 pathway plays a key role in mediating TGF-beta1 inhibition of branching morphogenesis and induction of connective tissue growth factor (CTGF) expression in embryonic lungs. Because a number of cell-specific interactions have been described between TGF-beta1-driven Smad signaling and the c-Jun N-terminal kinase (JNK) pathway, we have investigated the effects of JNK inhibition on TGF-beta1 activation of Smad2, inhibition of branching, induction of CTGF expression, and apoptosis in mouse embryonic lung explants. Mouse embryonic day 12.5 (E12.5) lung explants were treated with TGF-beta1 in the presence or absence of a specific pharmacologic JNK inhibitor (SP600125) and a specific JNK peptide inhibitor (JNKI). We found that TGF-beta1 activated the JNK pathway by stimulating c-Jun phosphorylation, which was blocked by JNK inhibitors. Treatment with SP600125 stimulated Smad2 phosphorylation and enhanced TGF-beta1-induced Smad2 phosphorylation. Treatment with JNK inhibitors also decreased normal branching morphogenesis and induced CTGF expression as well as augmented TGF-beta1 inhibition of branching and induction of CTGF expression. Furthermore, JNK inhibition-induced apoptosis. Our results demonstrate that inhibition of the JNK pathway promotes TGF-beta1-driven Smad2 responses in lung branching morphogenesis. These data suggest that the JNK pathway may antagonize TGF-beta1 dependent Smad2 signaling during mouse embryonic lung development.
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PMID:Inhibition of JNK enhances TGF-beta1-activated Smad2 signaling in mouse embryonic lung. 1912 19

Cleft palate represents one of the major congenital birth defects in humans. Despite the essential roles of ectodermal canonical Wnt and mesenchymal Wnt signaling in the secondary palate development, the function of mesenchymal canonical Wnt activity in secondary palate development remains elusive. Here we show that Gpr177, a highly conserved transmembrane protein essential for Wnt trafficking, is required for secondary palate development. Gpr177 is expressed in both epithelium and mesenchyme of palatal shelves during mouse development. Wnt1(Cre)-mediated deletion of Gpr177 in craniofacial neural crest cells leads to a complete cleft secondary palate, which is formed mainly due to aberrant cell proliferation and increased cell death in palatal shelves. By BATGAL staining, we reveal an intense canonical Wnt activity in the anterior palate mesenchyme of E12.5 wild-type embryos but not in Gpr177(Wnt1-Cre) embryos, suggesting that mesenchymal canonical Wnt signaling activated by Gpr177-mediated mesenchymal Wnts is critical for secondary palate development. Moreover, phosphorylation of JNK and c-Jun is impaired in the Gpr177(Wnt1-Cre) palate and is restored by implantation of Wnt5a-soaked beads in the in vitro palate explants, suggesting that Gpr177 probably regulates palate development via the Wnt5a-mediated noncanonical Wnt pathway in which c-Jun and JNK are involved. Importantly, certain cellular processes and the altered gene expression in palates lacking Gpr177 are distinct from that of the Wnt5a mutant, further demonstrating involvement of other mesenchymal Wnts in the process of palate development. Together, these results suggest that mesenchymal Gpr177 is required for secondary palate development by regulating and integrating mesenchymal canonical and noncanonical Wnt signals.
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PMID:Gpr177-mediated Wnt Signaling Is Required for Secondary Palate Development. 2592 32


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