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)

The expression and function of several proto-oncogenes were examined in a human acute T cell leukemia line, JURKAT, during phorbol ester-induced terminal differentiation. Treating JURKAT cells with the phorbol ester tetradecanoyl phorbol acetate (TPA) inhibited their proliferation and induced expression of the gene for the interleukin 2 receptor alpha chain (IL2R-alpha), consistent with previous reports. In unstimulated proliferating JURKAT cells, high levels of C-MYC, N-RAS, and BCL2 mRNAs were found that diminished rapidly following TPA-induced cessation of growth. In contrast, accumulation of mRNAs for the C-FOS, C-JUN, and EGR-1 genes increased markedly in TPA-treated cells and preceded the induction of IL2R-alpha mRNA. Expression of C-MYB, C-RAF-1, C-LCK, C-FYN, and C-FGR proto-oncogenes was relatively unchanged. To explore directly the function of two of these protooncogenes in regulating the growth of JURKAT T cells, we stably transferred C-MYC and BCL2 expression plasmids into these cells. Despite sustained expression of C-MYC, BCL2, or the combination of these protooncogenes, TPA continued to inhibit JURKAT cell growth and to induce IL2R expression. Thus, although C-MYC and BCL2 proto-oncogene expression correlated with proliferation in TPA-treated JURKAT cells, continuous over-expression of even the combination of these oncogenes was insufficient for abrogating the effects of TPA in these leukemic T cells. Because human lymphoid malignancies frequently contain chromosomal translocations that deregulate the expression of C-MYC and BCL2, our findings could have relevance for attempts to induce terminal differentiation of leukemic cells by in vitro exposure of patients' bone marrow cells to phorbol esters.
 ...
PMID:Phorbol ester-mediated inhibition of growth and regulation of proto-oncogene expression in the human T cell leukemia line JURKAT. 201 1

We investigated the effects of intracerebroventricular injection of angiotensin II on neuronal immediate early gene-encoded protein synthesis in the brain of conscious rats. The expression of seven immediate early gene-encoded transcription factors (c-Fos, FosB, c-Jun, JunB, JunD, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif/268) was assessed simultaneously. Angiotensin II (1, 10, 100 ng) induced a dose-dependent expression of c-Fos and Krox-24 in the subfornical organ, the median preoptic area and in the paraventricular nucleus and supraoptic nucleus of the hypothalamus, regions known to be involved in the central osmoregulatory and neuroendocrine actions of angiotensin II. FosB expression was induced four hours after icv injection of the highest dose of angiotensin II in the median preoptic area and paraventricular nucleus, c-Jun expression was restricted to the median preoptic area, subfornical organ and paraventricular nucleus, and JunB was only induced in the median preoptic area and subfornical organ. In these above mentioned regions, JunD exhibited a high basal staining, which was not visibly altered by angiotensin II. Krox-20 was not induced by angiotensin II. Intracerebroventricular injections of isotonic saline did not induce immediate early gene expression in any of the above brain areas. The angiotensin II-AT1 receptor antagonist, losartan, applied intracerebroventricular five minutes prior to angiotensin II, prevented the angiotensin II-induced immediate early gene protein expression. Losartan alone had no effects on immediate early gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Angiotensin II induces a complex activation of transcription factors in the rat brain: expression of Fos, Jun and Krox proteins. 775 10

delta-9-Tetrahydrocannabinol (THC) is a major psychoactive component of cannabis. We have recently localized a receptor for THC in the forebrain and found in the caudate-putamen that its gene expression is modulated by glucocorticoids, dopamine and glutamate. Here, we report for the first time, using quantitative in situ hybridization, that acute THC (5 mg kg-1, i.p.) regulates the mRNA levels of multiple immediate early genes in the adult rat forebrain. Twenty minutes after a single THC injection, significant increases in concentration of the mRNAs for C-FOS, C-JUN and ZIF-268 were observed in the cingulate cortex (75, 45 and 37%) and for C-FOS and ZIF-268 in the fronto-parietal cortex (60 and 64%) and caudate-putamen (81 and 32%) while JUN-D mRNA levels were not changed. These transcription factor genes might mediate putative THC modulation of neurotransmitter gene expression.
 ...
PMID:Activation of multiple transcription factor genes by tetrahydrocannabinol in rat forebrain. 791 80

NGFI-A is an immediate-early gene that encodes a transcription factor whose DNA-binding domain is composed of three zinc fingers. To define the domains responsible for its transcriptional activity, a mutational analysis was conducted with an NGFI-A molecule in which the zinc fingers were replaced by the GAL4 DNA-binding domain. In a cotransfection assay, four activation domains were found within NGFI-A. Three of the activation domains are similar to those characterized previously: one contains a large number of acidic residues, another is enriched in proline and glutamine residues, and another has some sequence homology to a domain found in Krox-20. The fourth bears no resemblance to previously described activation domains. NGFI-A also contains an inhibitory domain whose removal resulted in a 15-fold increase in NGFI-A activity. This increase in activity occurred in all mammalian cell types tested but not in Drosophila S2 cells. Competition experiments in which increasing amounts of the inhibitory domain were cotransfected along with NGFI-A demonstrated a dose-dependent increase in NGFI-A activity. A point mutation within the inhibitory domain of the competitor (I293F) abolished this property. When the analogous mutation was introduced into native NGFI-A, a 17-fold increase in activity was observed. The inhibitory effect therefore appears to be the result of an interaction between this domain and a titratable cellular factor which is weakened by this mutation. Downmodulation of transcription factor activity through interaction with a cellular factor has been observed in several other systems, including the regulation of transcription factor E2F by retinoblastoma protein, and in studies of c-Jun.
 ...
PMID:Transcriptional activity of the zinc finger protein NGFI-A is influenced by its interaction with a cellular factor. 841 79

This article reviews findings up to the end of 1997 about the inducible transcription factors (ITFs) c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif268); and the constitutive transcription factors (CTFs) CREB, CREM, ATF-2 and SRF as they pertain to gene expression in the mammalian nervous system. In the first part we consider basic facts about the expression and activity of these transcription factors: the organization of the encoding genes and their promoters, the second messenger cascades converging on their regulatory promoter sites, the control of their transcription, the binding to dimeric partners and to specific DNA sequences, their trans-activation potential, and their posttranslational modifications. In the second part we describe the expression and possible roles of these transcription factors in neural tissue: in the quiescent brain, during pre- and postnatal development, following sensory stimulation, nerve transection (axotomy), neurodegeneration and apoptosis, hypoxia-ischemia, generalized and limbic seizures, long-term potentiation and learning, drug dependence and withdrawal, and following stimulation by neurotransmitters, hormones and neurotrophins. We also describe their expression and possible roles in glial cells. Finally, we discuss the relevance of their expression for nervous system functioning under normal and patho-physiological conditions.
 ...
PMID:Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. 985 69

The specific signaling connections between the mitogen-activated protein kinases (MAPK) such as c-Jun N-terminal kinase (JNK-1) and phosphatases PP4 and M3/6, affecting the family of early nuclear factors, is complex and remains poorly understood. JNK-1 regulates cellular differentiation, apoptosis and stress responsiveness by up-regulating early nuclear factors such as c-Jun, a member of the activating protein (AP-1) family, and the Early Growth Factor (EGR-1). C-Jun, when phosphorylated by c-Jun N-terminal kinase (JNK-1) associates with c-Fos to form the AP-1 transcription factor that activates gene expression. We have investigated the regulation of the JNK-1 kinase by co-transfecting phosphatases PP4 and M3/6 in prostate cancer cell lines PC-3 and LNCaP, which have been previously stimulated with human EGF or cisplatin. Co-transfections of plasmids expressing the JNK-1 and the serine/threonine phosphatases PP4 resulted in a significant increase in JNK-1 activity in both PC3 and LNCaP cells. In contrast, co-transfection of JNK-1 with the dual specific phosphatase serine/threonine M3/6 showed only a marginal effect in JNK-1 activity. The phosphatase M3/6 also failed in blocking the induction of JNK-1 activity observed in presence of PP4. The higher activity of JNK-1 was associated with increased activities of the factors c-Jun/AP-1 and EGR-1. This suggests that JNK-1 activity in PC-3 and LNCaP cells requires not only active PP4 for stable maintenance but also suggests that the relative degree of phosphorylation of multiple cellular components is the determinant of JNK-1 stability.
 ...
PMID:Role of the phosphatase PP4 in the activation of JNK-1 in prostate carcinoma cell lines PC-3 and LNCaP resulting in increased AP-1 and EGR-1 activity. 1623 95

Deep brain stimulation is associated with delayed improvement of parkinsonian symptoms, such as hypokinesia with subthalamic nucleus stimulation, or dystonia with globus pallidus internus stimulation. The latency observed is better explained by molecular alterations than immediate electrophysiological processes, and clinical improvement may involve adaptive gene expression. Here, we have studied immediate early gene expression as fast molecular response to subthalamic nucleus stimulation. Bipolar electrodes were implanted bilaterally into the subthalamic nucleus of anesthetized male Wistar rats. High-frequency stimulation (130 Hz or 80 Hz, 60 micros, 300 microA) or low-frequency stimulation (5 Hz, 60 micros, 300 microA) was performed with the right electrode for 15, 60, 120, and 240 min whereas the silent left electrode served as negative control. Brains were fixed by transcardial perfusion and frozen sections were stained with polyclonal antibodies directed against three immediate early gene-encoded proteins, c-Fos, c-Jun, and Krox-24 (NGFI-A, Egr-1, Zif268, Tis8, Zenk). After 120 and 240 h, c-Fos immunoreactivity was strongly upregulated in subthalamic nucleus neurons on the stimulated site. In contrast, no c-Fos immunoreactivity was detected on the non-stimulated site except for single positive cells located in close proximity to the electrode tracks. Furthermore, c-Fos immunoreactivity was induced in subthalamic nucleus projection areas, such as primary and secondary motor cortex, primary somatosensory and insular cortex, lateral and medial globus pallidus, suprageniculate thalamic nucleus, pontine nuclei, medial geniculate nucleus, and substantia nigra. Similarly, c-Jun and Krox-24 were induced at the site of stimulation and in projection areas following high-frequency subthalamic nucleus stimulation. Whereas high frequency stimulation with 80 Hz was similarly effective none of the three immediate early gene-encoded proteins was induced with low-frequency stimulation (5 Hz) for 4 h. This is in accordance with the therapeutic effects of deep brain stimulation which are only elicited with high frequency stimulation. Our data provide evidence that immediate early gene expression in the subthalamic nucleus is rapidly and substantially induced by high-frequency stimulation. The induction of immediate early genes in projection sites suggests ipsilateral transsynaptic modulation of neuronal activity.
 ...
PMID:Induction of immediate early gene expression by high-frequency stimulation of the subthalamic nucleus in rats. 1646 Aug 81

Atypical antipsychotic drugs, such as olanzapine, have been reported to activate the locus coeruleus (LC) and lead to acute expression of the Fos-like immediate early gene (IEG) protein in the LC and medial prefrontal cortex (mPFC). Stimuli that activate the LC have been reported to increase expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. However, the effects of chronic treatment with olanzapine on IEG expression and the dose-dependence of the effects of olanzapine on IEG and TH expression are not known. Thus, we examined Fos-like, c-Jun, activating transcription factor 2 (ATF-2), early growth response 1 (Egr-1), early growth response 2 (Egr-2), and TH immunoreactivity expression in the LC and mPFC in rats receiving 2, 4, 8, or 15 mg/kg/day olanzapine by s.c. osmotic minipump for 4 h, 1 week, 2 weeks, or 4 weeks. ATF-2 expression was up-regulated at all treatment durations, while Egr-1 and Egr-2 were down-regulated in both the LC and mPFC. Fos-like expression was up-regulated through 2 weeks, but not 4 weeks, in both the LC and mPFC. C-Jun expression was up-regulated for 4 weeks in the LC and for 2 weeks, but not 4 weeks, in the mPFC. At all doses, there were rapid and sustained increases in TH immunoreactivity in the LC, but only delayed increases in the mPFC. These data indicate that olanzapine has rapid effects on IEG in the LC and mPFC, many of which are sustained through four weeks of treatment. Further, these data indicate that the delayed increase in TH expression in the mPFC parallels, and may play an important role in, the increased efficacy of olanzapine that emerges over time in humans.
 ...
PMID:Effects of short-term and chronic olanzapine treatment on immediate early gene protein and tyrosine hydroxylase immunoreactivity in the rat locus coeruleus and medial prefrontal cortex. 1697 29

The proinflammatory cytokine interleukin (IL)-1 activates several hundred genes within the same cell. This occurs in part by activation of the MKK7-JNK-c-Jun signaling pathway whose precise role in the regulation of individual inflammatory genes is still incompletely understood. To identify the genes that are under specific control of activated JNK, we used a JNK-MKK7 fusion protein. Genome-wide microarray analysis revealed EGR-1 as the transcript that was most strongly induced by JNK-MKK7. IL-1-stimulated EGR-1 mRNA and protein expression were impaired in cells lacking JNK or c-Jun. Transcriptional activation of the EGR-1 promoter by JNK-MKK7 or by IL-1 required a single upstream AP-1 site and three distal serum-response elements (SRE). Reconstitution experiments in c-Jun-deficient cells revealed that c-Jun is required for EGR-1 transcription through both the AP-1 site and the distal SREs. By chromatin immunoprecipitation analysis, we found IL-1-inducible recruitment of c-Jun to the AP-1 site and to the region containing the three distal SREs. These experiments suggest that c-Jun plays a dual role in EGR-1 transcription. It directly binds to the AP-1 element, and at the same time it is essential for promoter activation through the three distal SREs by an indirect unknown mechanism. As predicted by TRANSFAC analysis and verified by ChIP experiments, IL-1-induced EGR-1 protein binds to the promoter regions of inflammatory mediators such as IL-6, IL-8, and CCL2. Furthermore, short interfering RNA-mediated suppression of EGR-1 partially suppresses IL-1-inducible transcription of IL-8, IL-6, and CCL2. In summary, we provide novel evidence for a complex c-Jun-mediated mechanism that is essential for inducible EGR-1 expression. We identify this pathway as a previously unrecognized part of a multistep gene regulatory network that controls cytokine and chemokine expression via the IL-1-MKK7-JNK-c-Jun-EGR-1 pathway.
 ...
PMID:Transcriptional regulation of EGR-1 by the interleukin-1-JNK-MKK7-c-Jun pathway. 1828 87

The proapoptotic BH3-only protein Bim is a crucial regulator of neuronal apoptosis. Previous studies have indicated the involvement of the c-Jun, FOXO1/3a, and B/C-Myb transcription factors in the regulation of Bim during neuronal apoptosis. However, the mechanism underlying the transcriptional regulation of Bim in activity deprivation-induced neuronal apoptosis has remained unclear. The present study demonstrates that early growth response 1 (Egr-1), rather than c-Jun, FOXO1/3a, or B/C-Myb, directly transactivates Bim gene expression to mediate apoptosis of rat cerebellar granule neurons. We showed that Egr-1 was sufficient and necessary for neuronal apoptosis. Suppression of Egr-1 activity using dominant-negative mutant or knockdown of Egr-1 using small interfering RNAs led to a decrease in Bim expression, whereas overexpression of Egr-1 resulted in induction of Bim. Deletion and site-directed mutagenesis of the Bim promoter revealed that Bim transcriptional activation depends primarily on a putative Egr-binding sequence between nucleotides -56 and -47 upstream of the start site. We also showed that Egr-1 binding to this sequence increased in response to activity deprivation in vitro and in vivo. Moreover, inhibition of Egr-1 binding to the Bim promoter, by mithramycin A and chromomycin A3, reduced the activity deprivation-induced increases in Bim promoter activity and mRNA and protein levels and protected neurons from apoptosis, further supporting the Egr-1-mediated transactivation of Bim. Additionally, Bim overcame the Egr-1 knockdown-mediated inhibition of apoptosis, whereas Bim knockdown impaired the increase in apoptosis induced by Egr-1. These findings establish Bim as an Egr-1 target gene in neurons, uncovering a novel Egr-1/Bim pathway by which activity deprivation induces neuronal apoptosis.
 ...
PMID:Egr-1 transactivates Bim gene expression to promote neuronal apoptosis. 2145 Oct 41


1 2 Next >>