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PubMed1988

A gene activated by growth factors is related to the oncogene v-jun.

We have recently identified by cDNA cloning a set of genes that are rapidly activated in cultured mouse cells by protein growth factors. Here we report that the nucleotide sequence of a cDNA (clone 465) derived from one of these immediate early genes (hereafter called jun-B) encodes a protein homologous to that encoded by the avian sarcoma virus 17 oncogene v-jun. Homology between the jun-B and v-jun proteins is in two regions: one near the N terminus and the other at the C terminus. The latter sequence was shown by Vogt et al. [Vogt, P. K., Bos, T. J. & Doolittle, R. F. (1987) Proc. Natl. Acad. Sci. USA 84, 3316-3319] to have regions of sequence similarity to the DNA-binding domain of the yeast transcriptional regulatory protein GCN4 and to the oncogenic protein fos. Southern blots of human, mouse, and chicken DNA demonstrate that jun-B and c-jun are different genes and that there may be other vertebrate genes related to jun-B and c-jun. These findings suggest that there is a jun family of genes encoding related transcriptional regulatory proteins. The jun-B protein, and perhaps other members of the jun family, may play a role in regulating the genomic response to growth factors.

Amino Acid Sequence↗
PubMed1997

Involvement of c-JUN in the regulation of terminal differentiation genes in normal and malignant keratinocytes.

In stratifying cultures of human keratinocytes, expression of the proto-oncoprotein c-JUN and the small proline rich 2 (SPRR2) protein, a precursor of the cornified cell envelope, are inversely related. Whereas c-JUN is typically found in basal proliferating cells, SPRR2 is restricted to suprabasal differentiating layers. Malignant keratinocytes (derived from squamous cell carcinoma, SCC) have reduced sprr2 expression, consistent with their low potential to differentiate, and express c-jun at higher levels than normal keratinocytes. A direct relation between c-jun and sprr2 expression was shown in several ways: transient ectopic expression of c-jun inhibits sprr2a promoter activity in normal differentiating cells, whereas in malignant keratinocytes a dominant negative c-jun mutant restored at least partially both the low promoter activity and the expression of endogenous sprr2. These effects are mediated via a 134 bp promoter fragment which does not include the sprr2a AP-1 binding site. Interestingly, in an SCC cell line, constitutively expressing the dominant c-jun mutant, expression of the terminal differentiation marker involucrin is also strongly increased, suggesting that c-JUN is a general modulator of keratinocyte terminal differentiation rather than only affecting the expression of sprr2.

Carcinoma, Squamous Cell↗
PubMed1997

Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases.

The proto-oncogene-encoded transcription factor c-Jun activates genes in response to a number of inducers that act through mitogen-activated protein kinase (MAPK) signal transduction pathways. The activation of c-Jun after phosphorylation by MAPK is accompanied by a reduction in c-Jun ubiquitination and consequent stabilization of the protein. These results illustrate the relevance of regulated protein degradation in the signal-dependent control of gene expression.

3T3 Cells↗
PubMedDate not supplied

In vivo effects of adrenocorticotropin on c-jun, jun-B, c-fos and fos-B in rat adrenal.

We have studied the in vivo effects of adrenocorticotropin (ACTH) on mRNA levels of c-jun, jun-B, c-fos and fos-B, in rat adrenals. In control rats, c-jun mRNA was abundant in both zona glomerulosa (ZG) and zona fasciculatareticularis (ZF-R). Although less abundant than c-jun, the mRNA of jun-B could be detected in both zones, whereas that of c-fos could barely be detected and that of fos-B could not. After an injection with short acting ACTH, mRNA levels of c-jun, c-fos, jun-B and fos-B were maximally increased in both zones within 30 min. Within 5h, the mRNA levels decreased towards control levels for c-jun, to below control levels for jun-B, and to undetectable levels for c-fos and fos-B. After a sustained stimulation by two daily administrations of long acting ACTH, the mRNA of c-jun was still abundant in both zones, although its level decreased by 50% and 80% after 36h and 9 days, respectively, after the first injection. Under such conditions, the mRNA level of jun-B was increased, that of fos-B could barely be detected, and that of c-fos could not be detected. To conclude, these results suggest that jun-B, fos-B, and also c-fos play a role in triggering early events leading to an increased steroidogenesis, as well as a basic role in maintaining the integrity of the adrenal cortex in the case of c-jun and jun-B.

Adrenal Glands↗
PubMed1998

Possible role of c-Jun in transcription of the mouse renin gene.

BACKGROUND: Renin is a rate-limiting enzyme for activity of the circulating renin-angiotensin system (RAS) and expression of the renin gene is regulated by a variety of stimuli. In this study, we examined a possible role of c-Jun in the transcription of renin gene. METHODS: The renin promoter, chloramphenicol acetyltransferase (CAT), fusion genes with or without c-Jun expression vector (pSV-c-Jun) were transfected into human embryonic kidney (HEK) cells, and the effects of c-Jun were examined by deletion and mutation analyses of CAT assay and by in vitro transcription-primer extension assay. We also examined the effects of c-Jun on DNA-binding activity to the renin promoter by electrophoretic mobility shift assay (EMSA). Furthermore, we examined the effects of c-Jun on transcription of the renin gene in enriched juxtaglomerular (JG) cells by cotransfection with pSV-c-Jun and by treatment with antisense c-jun oligodeoxynucleotides. RESULTS: Promoter activity of the renin gene was increased by c-Jun overexpression in HEK cells, and the proximal promoter region from -47 to +16 was sufficient for transcriptional activation by c-Jun. Although mutation of activator protein-1 (AP-1) element-like sequences in the proximal promoter did not affect c-Jun-mediated stimulation, mutation of the core promoter including the TATA box inhibited c-Jun-mediated transcription. The results of EMSA showed that c-Jun overexpression produced a binding of nuclear factor, which was HEK cell-specific and distinct from TATA box-binding protein and AP-1 family transcription factor, to the renin core promoter region (RC element) from -36 to -20. The overexpression of c-Jun activated the renin promoter in renin-expressing JG cells, and antisense c-jun decreased the activity of renin promoter and expression of renin mRNA in JG cells. CONCLUSIONS: These results indicate that the RC element plays a role in c-Jun-mediated transcriptional regulation of the renin gene in HEK cells, and suggest that c-Jun participates in the regulation of renin gene expression in JG cells of the kidney.

Animals↗
PubMed1992

Analysis of glutathione transferase P gene regulation with liver cells in primary culture.

Glutathione transferase P (GST-P) gene is specifically and highly activated during rat chemical hepatocarcinogenesis. We have previously cloned the GST-P gene and have identified putative regulatory regions. To further explore regulatory mechanisms, deletion constructs of the GST-P gene fused to the chloramphenicol acetyltransferase (CAT) structural gene were introduced into primary cultured rat hepatocytes by electroporation, and their activity was determined. The expression of the GST-P-CAT fusion gene is quite low in these cells as compared to that in both a rat fibroblast cell line, 3Y1 cells, and a rat hepatoma cell line, dRLh84. The presence of the strong enhancer GPEI did not elicit any enhancing activity at its original position, or when it was located 3' of the CAT gene, although this element does enhance CAT activity significantly when located adjacent to the promoter. Cotransfection of neither c-jun nor c-fos expression vector, nor both vectors, could enhance the CAT activity, even though GPEI consists of two phorbol ester response element-like sites. Furthermore, the expression of jun family gene was not correlated with GST-P gene expression either in primary cultured hepatocytes or in hepatoma cell lines.

Animals↗
PubMed2003

The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene.

The c-Jun dimerization protein, JDP2, is a member of the AP-1 (activating protein-1) family of the basic leucine zipper transcription factors. JDP2 can bind 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive element and cAMP-responsive element DNA response elements, resulting in the inhibition of transcription. Although the role of AP-1 in cell proliferation and malignant transformation is well established, the role of JDP2 in this process is of subject to debate. On the one hand, JDP2 was shown to inhibit cyclin D transcription and promote differentiation of skeletal muscle and osteoclast cells. On the other hand, JDP2 was shown to partially transform chicken embryo fibroblast and was identified in a screen for oncogenes able to collaborate with the loss of p27kip cyclin-dependent inhibitor to induce lymphomas. Using cell transformation assays in NIH3T3 cells and injection of prostate cancer cell lines overexpressing JDP2 into severe combined immuno-deficient (SCID) mice, we show for the first time the potential role of JDP2 in inhibition of cell transformation and tumor suppression. The mechanism of tumor suppressor action of JDP2 can be partially explained by the generation of inhibitory AP-1 complexes via the increase of JunB, JunD, and Fra2 expression and decrease of c-Jun expression.

Animals↗
PubMed2002

A mutant epidermal growth factor receptor targeted to lung epithelium inhibits asbestos-induced proliferation and proto-oncogene expression.

Asbestos is a ubiquitous naturally occurring fiber causing multiple cancers and fibroproliferativedisease. The mechanisms of epithelial cell hyperplasia, a hallmark of the initiation of lung cancers by asbestos, have been unclear. We demonstrate here that mice expressing a dominant-negative mutant epidermal growth factor receptor (EGFR) under the control of the human lung surfactant protein-C promoter exhibit decreased pulmonary epithelial cell proliferation without alterations in asbestos-induced inflammation. In contrast to transgene-negative littermates, inhalation of asbestos by mice expressing the mutant EGFR does not result in early and elevated expression of early response proto-oncogenes (fos/jun or activator protein 1 family members). Additionally, quantitative reverse transcriptase-PCR analysis for levels of c-jun and c-fos in bronchiolar epithelium isolated by laser capture microdissection demonstrates increases in expression of these genes in asbestos-exposed epithelial cells. Results show that the EGFR mediates both asbestos-induced proto-oncogene expression and epithelial cell proliferation, providing a rationale for modification of its phosphorylation in preventive and therapeutic approaches to lung cancers and mesothelioma.

Administration, Inhalation↗
PubMed1994

SV40 large T antigen with c-Jun down-regulates myelin P0 gene expression: a mechanism for papovaviral T antigen-mediated demyelination.

Expression of myelin proteins has been shown to be altered in transgenic mice that express papovaviral large tumor (T) antigens. This paper analyzes the effect on P0 gene expression in secondary Schwann cells transfected with the SV40 T antigen gene and in Schwann cells immortalized by T antigen. In secondary Schwann cells, both T antigen and c-Jun are required for significant inhibition of the P0 promoter; expression of only one of the proteins is insufficient for repression of the P0 gene. T antigen, c-Jun (p39), and c-Jun-related protein (p47) form an immunoprecipitable complex in SV40 immortalized Schwann cell lines, and T antigen and c-Jun bind independently and as a complex to the P0 promoter. Our data suggest that the probable molecular mechanism underlying the hypomyelination observed in transgenic animals expressing T antigen may be due to the repression of the P0 gene by T antigen and c-Jun.

Animals↗
PubMed1998

UV irradiation induces the murine urokinase-type plasminogen activator gene via the c-Jun N-terminal kinase signaling pathway: requirement of an AP1 enhancer element.

UV irradiation leads to severe damage, such as cutaneous inflammation, immunosuppression, and cancer, but it also results in a gene induction protective response termed the UV response. The signal triggering the UV response was thought to originate from DNA damage; recent findings, however, have shown that it is initiated at or near the cell membrane and transmitted via cytoplasmic kinase cascades to induce gene transcription. Urokinase-type plasminogen activator (uPA) was the first protein shown to be UV inducible in xeroderma pigmentosum DNA repair-deficient human cells. However, the underlying molecular mechanisms responsible for the induction were not elucidated. We have found that the endogenous murine uPA gene product is transcriptionally upregulated by UV in NIH 3T3 fibroblast and F9 teratocarcinoma cells. This induction required an activator protein 1 (AP1) enhancer element located at -2.4 kb, since deletion of this site abrogated the induction. We analyzed the contribution of the three different types of UV-inducible mitogen-activated protein (MAP) kinases (ERK, JNK/SAPK, and p38) to the activation of the murine uPA promoter by UV. MEKK1, a specific JNK activator, induced transcription from the uPA promoter in the absence of UV treatment, whereas coexpression of catalytically inactive MEKK1(K432M) and of cytoplasmic JNK inhibitor JIP-1 inhibited UV-induced uPA transcriptional activity. In contrast, neither dominant negative MKK6 (or SB203580) nor PD98059, which specifically inhibit p38 and ERK MAP kinase pathways, respectively, could abrogate the UV-induced effect. Moreover, our results indicated that wild-type N-terminal c-Jun, but not mutated c-Jun (Ala-63/73), was able to mediate UV-induced uPA transcriptional activity. Taken together, we show for the first time that kinases of the JNK family can activate the uPA promoter. This activation links external UV stimulation and AP1-dependent uPA transcription, providing a transcription-coupled signal transduction pathway for the induction of the murine uPA gene by UV.

3T3 Cells↗
PubMed1993

Display of biologically active proteins on the surface of filamentous phages: a cDNA cloning system for selection of functional gene products linked to the genetic information responsible for their production.

A cloning and expression system allowing display of functional cDNAs or other gene products on the surface of filamentous phage has been developed, exploiting the high-affinity interaction of the Jun and Fos leucine zippers. Gene jun was expressed from a lacZ promoter as a fusion protein with the viral coat protein, pIII, thereby being structurally incorporated into phage particles during infection with a helper phage. Using a second lacZ promoter of the phagemid, gene fos was co-expressed as an N-terminal fusion peptide to cDNA library gene products, so that the resulting Fos-fusion proteins could become associated with the Jun-decorated phage particles. To avoid interphage exchange of fos-cDNA fusion products, cysteines were engineered at the N- and C-termini of each of the leucine zippers, providing a covalent link of the cDNA gene product to the genetic instructions required for its production. Dissociation between phage and cDNA gene products was readily achieved using reducing agents. Phages displaying gene products covalently anchored on their surface via the modified leucine zippers can be selectively enriched 10(4)-10(6)-fold over nonspecific phages using antibodies. Thus, this cloning system allows rapid isolation of rare mRNA products from complex cDNA libraries by enrichment with appropriate ligands. This approach should allow the expression and cloning of dimeric proteins by cDNA shuffling.

Amino Acid Sequence↗
PubMed2005

Acute phase gene expression in mice exposed to the marine neurotoxin domoic acid.

Domoic acid is a rigid analog of the neurotransmitter glutamate and a potent agonist of kainate subtype glutamate receptors. Persistent activation of these receptor subtypes results in rapid excitotoxicity, calcium dependent cell death and neuronal lesions in areas of the brain where kainate pathways are concentrated. To better understand responses to domoic acid induced excitotoxicity, microarrays were used to profile gene expression in mouse brain following domoic acid exposure. Adult female mice were subjected intraperitoneally to domoic acid at the lethal dose 50, killed and dissected at 30, 60 and 240 min post-injection. Total brain RNA from treated mice was compared with time-matched controls on Agilent 22K feature microarrays. Real-time PCR was performed on selected genes. For the 30, 60 and 240 min time points, 3.96%, 3.94% and 4.36% of the genes interrogated were differentially expressed (P-value < or = 0.01), respectively. Rigorous filtering of the data resulted in a set of 56 genes used for trending analysis and K-medians and agglomerative clustering. The earliest genes induced consisted primarily of early response gene families (Jun, Fos, Ier, Egr, growth arrest and DNA damage 45) and the inflammatory response element cyclooxygenase 2. Some later responding genes involved glucocorticoid responses (Gilz, Sgk), cold inducible proteins (Cirbp, Rbm3), Map kinases (Map3k6) and NF-kappaB inhibition. Real-time PCR in male mice from an additional study confirmed the expression of several of these genes across gender. The transcriptional profile induced by domoic acid shared similarity with expression profiles of brain ischemia and other excitotoxins, suggesting a common transcriptional response.

Acute-Phase Reaction↗
PubMed2004

Activin type II receptor restoration in ACVR2-deficient colon cancer cells induces transforming growth factor-beta response pathway genes.

The activin type II receptor (ACVR2) gene is a putative tumor suppressor gene that is frequently mutated in microsatellite-unstable colon cancers (MSI-H colon cancers). ACVR2 is a member of the transforming growth factor (TGF)-beta type II receptor (TGFBR2) family and controls cell growth and differentiation. SMAD proteins are major intracellular effectors shared by ACVR2 and TGFBR2 signaling; however, additional shared effector mechanisms remain to be explored. To discover novel mechanisms transmitting the ACVR2 signal, we restored ACVR2 function by transfecting wild-type ACVR2 (wt-ACVR2) into a MSI-H colon cancer cell line carrying an ACVR2 frameshift mutation. The effect of ACVR2 restoration on cell growth, SMAD phosphorylation, and global molecular phenotype was then evaluated. Decreased cell growth was observed in wt-ACVR2 transfectants relative to ACVR2-deficient vector-transfected controls. Western blotting revealed higher expression of phosphorylated SMAD2 in wt-ACVR2 transfectants versus controls, suggesting cells deficient in ACVR2 had impaired SMAD signaling. Microarray-based differential expression analysis revealed substantial ACVR2-induced overexpression of genes implicated in the control of cell growth and tumorigenesis, including the activator protein (AP)-1 complex genes JUND, JUN, and FOSB, as well as the small GTPase signal transduction family members, RHOB, ARHE, and ARHGDIA. Overexpression of these genes is shared with TGFBR2 activation. This observed similarity between the activin and TGF-beta signaling systems suggests that activin may serve as an alternative activator of TGF-beta effectors, including SMADs, and that frameshift mutation of ACVR2 may contribute to MSI-H colon tumorigenesis via disruption of alternate TGF-beta effector pathways.

Activin Receptors, Type II↗
PubMed1994

Constitutive cJun expression induces partial macrophage differentiation in U-937 cells.

Previous studies have shown that phorbol ester induced macrophage differentiation in the leukemic cell line U-937 is tightly linked to the expression of the c-jun protooncogene and the generation of AP-1 transcriptional activity. We expressed the c-jun protooncogene in U-937 cells to examine the role of c-jun in the differentiation of these cells. AP-1 DNA binding activity and the expression of AP-1 controlled downstream genes were increased in all clones expressing exogenous cJun. More importantly, these transfectants showed evidence of differentiation as measured by the acquisition of phagocytic capacity, although they did not develop morphological changes associated with differentiation such as adherence. Furthermore, they became committed to terminal differentiation after significantly shorter exposures to phorbol esters than did control cell lines. These data show that cJun expression induces partial differentiation along the macrophage pathway in U-937 cells.

Animals↗
PubMed2006

Deletion of the c-Jun N-terminal kinase 3 gene protects neonatal mice against cerebral hypoxic-ischaemic injury.

c-Jun N-terminal kinase 3 (JNK3) is a member of the stress-activated group of mitogen-activated protein kinases. c-Jun N-terminal kinase 3 is a potent mediator of apoptosis and the use of JNK inhibitors or jnk3 gene deletion each protect against brain injury in adults. However, little is known about the role of JNK3 or its mechanism of action in neonatal brain injury. The aim of the present study was to compare the vulnerability of neonatal JNK3 knockout (JNK3 KO) mice and wild-type (WT) mice to cerebral hypoxic-ischaemic injury (HII) using unilateral-carotid occlusion combined with transient hypoxia. The degree of neural tissue loss in JNK3 KO mice was substantially reduced compared with WT mice (JNK3 KO 27.8%+/-2.8% versus WT 48.3%+/-2.0%, P<or=0.0001) after HII. Significant attenuation of injury was observed in the cerebral cortex, hippocampus, striatum, and thalamus of JNK3 KO compared with WT mice. Hypoxic-ischaemic injury increased JNK phosphorylation and activity, with JNK3 as the major isoform. Significantly, in JNK3 KO animals there was no difference in the activation of the upstream kinases mitogen-activated protein kinase kinase (MKK4) or MKK7. Downstream of JNK3, HII lead to increased phosphorylation of the transcription factors c-Jun and adenovirus transcription factor-2 (ATF-2), which was attenuated in JNK3 KO mice. c-Jun N-terminal kinase 3 deletion also decrease caspase-3 cleavage and Bim/PUMA expression, coupled with a upregulation of AKT/FOXO3a levels, linking JNK3 to apoptosis. These findings implicate JNK3 involvement in neural cell loss resulting from cerebral HII in the developing brain.

Activating Transcription Factor 2↗