Disease relevance of Jun

• Here we describe new findings concerning HIF-1-dependent c-Jun N-terminal phosphorylation in cells exposed to hypoxia or anoxia [1].
• Overexpression of manganese superoxide dismutase selectively modulates the activity of Jun-associated transcription factors in fibrosarcoma cells [2].
• Fos-Jun double-transgenic mice develop osteosarcomas at a higher frequency than single-Fos transgenic mice with no differences in the time of onset of tumor formation [3].
• c-Jun inhibits NF-E2 transcriptional activity in association with p18/maf in Friend erythroleukemia cells [4].
• Remarkably, subcutaneous injection of ES cells lacking c-Jun into syngeneic mice led to a drastic reduction in the formation of teratocarcinomas [5].

Psychiatry related information on Jun

• To further examine what role c-Fos may play in regulating sleep, the present study examined the effects of prolonged wakefulness on c-Fos and AP-1 activity in young (3.5 months old) and old (21.5 months old) Sprague--Dawley rats [6].
• Valproic acid (VPA), which has demonstrated efficacy in the treatment of bipolar disorder, has been shown to alter components of the phosphoinositide (PI) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 (AP-1) [7].

High impact information on Jun

• Primary hepatocytes lacking c-Jun showed increased sensitivity to TNF-alpha-induced apoptosis, which was abrogated in the absence of p53 [8].
• Liver-specific inactivation of c-Jun at different stages of tumor development was used to study its role in chemically induced hepatocellular carcinomas (HCCs) in mice [8].
• The transcription factor c-Jun mediates several cellular processes, including proliferation and survival, and is upregulated in many carcinomas [8].
• Here we show, by a knock-in strategy and a transgenic complementation approach, that Junb can substitute for absence of Jun during mouse development [9].
• JunB can substitute for Jun in mouse development and cell proliferation [9].

Chemical compound and disease context of Jun

• Induction of differentiation of F9 teratocarcinoma stem cells by retinoic acid and cAMP has been shown to involve the activation of the transcription factor AP-1 (a heterodimer of the proto-oncogene products c-Fos and c-Jun); moreover, stable expression of either Fos or Jun drives F9 cells into differentiation [10].
• Topical application of 10 mumol curcumin together with 5 nmol TPA once a day for 5 days strongly inhibited TPA-induced epidermal hyperplasia and c-Jun and c-Fos expression [11].
• Topical administration of a halofuginone-containing cream for 20 days to TSK mice, which spontaneously develop dermal fibrosis, greatly increased the phosphorylated form of c-Jun in the skin; this was followed by a decrease in skin thickness and type I collagen messenger RNA expression [12].
• All-trans-retinoic acid (RA) treatment of Jun-deficient, mouse F9, teratocarcinoma cells causes the induction of c-jun expression [13].
• This report examined the effects of c-jun and/or c-fos AP-1 protooncogenes and the glucocorticoid hormone dexamethasone on expression of the HPV 16 cGRE in AP-1-deficient P19 embryonal carcinoma cells [14].

Biological context of Jun

• Junb can rescue both liver and cardiac defects in Jun-null mice in a manner dependent on gene dosage [9].
• These data suggest that the proenkephalin gene may be a physiological target for Fos and Jun in the hippocampus and indicate that these proto-oncogene transcription factors may play a role in neuronal responses to stimulation [15].
• Different c-Jun N-terminal kinases (JNKs) are activated by a plethora of signals and phosphorylate substrates such as c-Jun, which is required for efficient cell cycle progression [16].
• JNK catalyzed phosphorylation of c-Jun was also detected in the acini [17].
• c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms [18].

Anatomical context of Jun

• The AP-1 transcription factor c-Jun is a key regulator of hepatocyte proliferation [19].
• We have used fibroblasts derived from c-Jun null embryos to define the role of c-Jun in two separate processes: cell growth and apoptosis [18].
• Since positive and negative selection of thymocytes during T-cell development also depends on activation through the T-cell receptor, Fos and Jun may play a role in thymocyte development as well [20].
• Overexpression of Fos and Jun from transiently transfected constructs resulted in a functional inhibition of the glucocorticoid receptor in these mouse mammary epithelial cells [21].
• Osteoblastic marker genes were expressed at varying levels in different cell lines, but expression of interstitial collagenase (matrix metalloproteinase-1) was enhanced in cells derived from Fos-Jun tumors [3].

Associations of Jun with chemical compounds

• This effect is likely to be elicited by the dimerization potential of the Jun leucine zipper trapping cellular Jun and/or Fos in a protein complex unable to bind to DNA [22].
• The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents [23].
• Glucose utilization is essential for hypoxia-inducible factor 1 alpha-dependent phosphorylation of c-Jun [1].
• The proto-oncogene transcription factors Fos and Jun form a heterodimeric complex that binds to DNA and regulates expression of specific target genes [24].
• Here, we demonstrate that CpG DNA induces the activation of c-Jun NH2-terminal kinase and p38 but does not activate the extracellular receptor kinase in murine B and monocyte-like cell lines [25].

Physical interactions of Jun

• Rather, c-Jun regulates transcription of p53 negatively by direct binding to a variant AP-1 site in the p53 promoter [26].
• JNK2 is preferentially bound to c-Jun in unstimulated cells, thereby contributing to c-Jun degradation [16].
• Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families [27].
• Antisera to Fos inhibits NF-AT DNA binding as does an oligonucleotide containing a binding site for AP1 [28].
• Pretreatment of wild-type cells with 5-iodo-6-amino-1,2-benzopyrone, a PARP-1 inhibitor, inhibited JNK activation and DNA binding of AP-1 [29].

Enzymatic interactions of Jun

• Indeed, adenoviral MKP-1 expression increased insulin expression by decreasing a phosphorylation form of JNKs and a resulting phosphorylated form of c-jun in MIN6 cells [30].
• MT-null mice were more sensitive than wild-type mice to cadmium-induced, stress-related gene expression, in accord with greater activation of transcription factor AP-1 and phosphorylated JNK and ERK [31].
• In an electrophoretic mobility shift assay, bands of the complexes were supershifted by addition of antibody to c-fos and phosphorylated c-jun [32].

Regulatory relationships of Jun

• Inactivation of p53 in c-jun (Deltali*) mice abrogated both hepatocyte cell cycle block and increased p21 protein expression [19].
• Furthermore, Fra-1 repressed AP-1 activity induced by either TPA or expression of c-Jun and c-Fos [33].
• TPA and EGF induce transactivation of AP-1 activity in P+ cells but not in P- cells [34].
• Furthermore, Jun neither enhanced nor inhibited down regulation by Fos [35].
• Overexpression of c-Jun protein (Jun) could not restore serum-induced DNA synthesis to cells expressing inducible anti-fos RNA despite equivalent transactivation of an AP-1 target gene [36].
• MEF2 and HDAC4 act to repress c-Jun expression in quiescent VSMCs, protein kinase A enhances this repression, and platelet-derived growth factor derepresses c-Jun expression through calcium/calmodulin-dependent protein kinases and novel protein kinase Cs [37].

Other interactions of Jun

• Here we show by retroviral-gene transfer that all four Fos proteins, but not the Jun proteins, rescue the differentiation block in vitro [38].
• Both AP1 and Myc are activated in fibroblasts in response to growth factor stimulation, and various experiments suggest their importance in proliferation [39].
• We have investigated several candidate pathways implicated in the regulation of p21 expression, and observed increased activity of the stress kinase p38 in regenerating livers of c-jun (Deltali*) mice [19].
• Consistently, liver regeneration was rescued in c-jun (Deltali*) p21 (-/-) double-mutant mice [19].
• Comparison of several myogenin mutants for their responsiveness to Fos and Jun shows that repression is directed at the basic-HLH region [40].

Analytical, diagnostic and therapeutic context of Jun

• Mammalian two-hybrid assays revealed high-affinity protein-protein interactions between c-Fos and c-Jun with steroidogenic factor 1, GATA-4, and CCAAT/enhancer binding protein-beta [41].
• Phosphorylation of the mitogen-activated protein kinases Erk and Jnk, and of their nuclear substrates Elk-1 and c-Jun, was examined by Western blot [42].
• Using site-directed mutagenesis and EMSA techniques, we identified an activation protein 1 (AP1)-like element (-134/-128; TGAATCA) in the AVP gene 5'-promoter region, which is the sole responsible site for the Fos/Jun-mediated transcription [43].
• Nuclear extracts from LPS-stimulated cells showed an increase in phosphorylated c-Jun by immunoblotting [44].
• We found that, among the curcumin derivatives examined, only inhibitors shown to inhibit the binding of Jun-Fos to DNA by Electrophoretic Mobility Shift Assay (EMSA) inhibited AP-1 transcriptional activity in vivo [45].

References