Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of cells with pro-inflammatory cytokines or ultraviolet radiation causes activation of the c-Jun NH2-terminal protein kinase (JNK). Activating transcription factor-2 (ATF2) was found to be a target of the JNK signal transduction pathway. ATF2 was phosphorylated by JNK on two closely spaced threonine residues within the NH2-terminal activation domain. The replacement of these phosphorylation sites with alanine inhibited the transcriptional activity of ATF2. These mutations also inhibited ATF2-stimulated gene expression mediated by the retinoblastoma (Rb) tumor suppressor and the adenovirus early region 1A (E1A) oncoprotein. Furthermore, expression of dominant-negative JNK inhibited ATF2 transcriptional activity. Together, these data demonstrate a role for the JNK signal transduction pathway in transcriptional responses mediated by ATF2.
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PMID:Transcription factor ATF2 regulation by the JNK signal transduction pathway. 782 38

Studies have demonstrated that the retinoblastoma susceptibility gene product, RB, can either positively or negatively regulate expression of several genes through cis-acting elements in a cell-type-dependent manner. The nucleotide sequence of the retinoblastoma control element (RCE) motif, GCCACC or CCACCC, and the Sp1 consensus binding sequence, CCGCCC, can confer equal responsiveness to RB. Here, we report that RB activates transcription of the c-jun gene through the Sp1-binding site within the c-jun promoter. Preincubation of crude nuclear extracts with monoclonal antibodies to RB results in reduction of Sp1 complexes in a mobility shift assay, while addition of recombinant RB in mobility shift assay mixtures with CCL64 cell extracts leads to an enhancement of DNA-binding activity of SP1. These results suggest that RB is directly or indirectly involved in Sp1-DNA binding activity. A mechanism by which RB regulates transactivation is indicated by our detection of a heat-labile and protease-sensitive Sp1 negative regulator(s) (Sp1-I) that specifically inhibits Sp1 binding to a c-jun Sp1 site. This inhibition is reversed by addition of recombinant RB proteins, suggesting that RB stimulates Sp1-mediated transactivation by liberating Sp1 from Sp1-I. Additional evidence for Sp1-I involvement in Sp1-mediated transactivation was demonstrated by cotransfection of RB, GAL4-Sp1, and a GAL4-responsive template into CV-1 cells. Finally, we have identified Sp1-I, a approximately 20-kDa protein(s) that inhibits the Sp1 complexes from binding to DNA and that is also an RB-associated protein. These findings provide evidence for a functional link between two distinct classes of oncoproteins, RB and c-Jun, that are involved in the control of cell growth, and also define a novel mechanism for the regulation of c-jun expression.
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PMID:The retinoblastoma gene product RB stimulates Sp1-mediated transcription by liberating Sp1 from a negative regulator. 800 47

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.
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PMID:Transcriptional activity of the zinc finger protein NGFI-A is influenced by its interaction with a cellular factor. 841 79

Examination of the nucleotide sequence of the retinoblastoma (Rb) promoter revealed the presence of a DNA region highly homologous to the recognition site for the cellular transcription factor AP-1. A pair of complementary oligonucleotides containing the AP-1 site was synthesized and used in gel retardation assays to determine the role of the AP-1 protein in the regulation of the Rb gene expression. Using nuclear extracts from Hela cells as well as from lung and bladder tumors, we found specific binding of the AP-1 protein to this oligonucleotide. This binding is elevated in Hela cells, in 10/13 lung and 3/8 bladder tumors as compared to adjacent normal tissue. These results suggest that AP-1 could be implicated in Rb gene transcriptional regulation through its interaction with the AP-1 binding site of the Rb gene promoter.
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PMID:Human lung and bladder carcinoma tumors as compared to their adjacent normal tissue have elevated AP-1 activity associated with the retinoblastoma gene promoter. 847 21

The antimicrobial, immunomodulatory, and cell growth-regulatory activities of the interferons are mediated by interferon-inducible proteins. One of these is p202, a nuclear protein that is encoded by the Ifi 202 gene from the interferon-activatable gene 200 cluster. Overexpression of p202 in transfected cells slows down cell proliferation. As shown earlier, p202 binds to the hypophosphorylated form of the retinoblastoma susceptibility protein. Here we report that p202 inhibits the activities of the NF-kappa B and the AP-1 enhancers both in transiently transfected cells and in transfected stable cell lines overexpressing p202. Furthermore, p202 binds the NF-kappa B p50 and p65 and the AP-1 c-Fos and c-Jun transcription factors in vitro and in vivo. NF-kappa B, c-Fos, and c-Jun participate in the transcription of various cellular and viral genes, and thus p202 can modulate the expression of these genes in response to interferons.
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PMID:The interferon-inducible p202 protein as a modulator of transcription: inhibition of NF-kappa B, c-Fos, and c-Jun activities. 852 15

The E7 gene product of human papillomavirus type 16 (HPV16) binds to the retinoblastoma gene product (pRb) and dissociates pRb-E2F complexes. However, the observation that the ability of E7 to bind pRb is not required for the HPV16-induced immortalization of primary keratinocytes prompted a search for other cellular factors bound by E7. Using a glutathione-S-transferase (GST) fusion protein system, we show that E7 complexes with AP1 transcription factors including c-Jun, JunB, JunD and c-Fos. The ability of E7 to complex with c-Jun in vivo is demonstrated by co-immunoprecipitation and the yeast two-hybrid system. An analysis of E7 point mutants in the GST system indicates that the E7 zinc-finger motif, but not the pRb binding domain, is involved in these interactions. Using c-Jun deletion mutants, E7 binding maps between amino acids 224 and 286 of c-Jun. E7 trans-activates c-Jun-induced transcription from a Jun responsive promoter, and this activity correlates with the ability of E7 mutants to bind Jun proteins. Finally, a transcriptionally inactive c-Jun deletion, which can bind E7, interferes with the E7-induced transformation of rat embryo fibroblasts in cooperation with an activated ras, indicating that the Jun-E7 interaction is physiologically relevant and that Jun factors may be targeted in the E7 transformation pathway.
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PMID:The human papillomavirus type 16 E7 gene product interacts with and trans-activates the AP1 family of transcription factors. 861 42

p202 is an interferon-inducible protein whose expression in transfected cells inhibits proliferation. p202 binds to the retinoblastoma tumor suppressor protein in vitro and in vivo and the transcription factors AP-1 c-Fos and c-Jun, NF-kappaB p50 and p65, and inhibits the transcriptional activity of these factors in vivo. Here we report that p202 nonspecifically binds to double-stranded DNA and to single-stranded DNA in vitro. Analysis with recombinant p202 revealed that DNA binding activity is intrinsic to p202. A C-terminal deletion mutant of p202 exhibited DNA-binding properties, indicating that the C-terminus is dispensable for DNA binding. We also found that underphosphorylated p202 efficiently binds to DNA. Our data suggest that DNA binding activity of p202 may contribute to its functions.
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PMID:The interferon-inducible growth-inhibitory p202 protein: DNA binding properties and identification of a DNA binding domain. 861 67

Angiotensin II (AII) binds to specific G protein-coupled receptors and is mitogenic in adrenal, liver epithelial, and vascular smooth muscle cells. Since the cyclin D1 gene encodes the regulatory subunit of the cyclin D1-dependent kinase (CD1K) required for phosphorylation of the retinoblastoma protein (pRB), an essential and rate-limiting step in G1 phase progression of the cell cycle, we examined the effect of AII on cyclin D1 expression and CD1K activity in the human adrenal cell line H295R. AII (10(-6) M) stimulated G1 phase progression within 12 h, with a maximal effect after 72 h. This action was antedated by the induction of cyclin D1 mRNA (3-fold), cyclin D1 nuclear protein abundance (4-fold), and CD1K activity (4-fold). AII induced cyclin D1 promoter activity 4-fold, via the AT1 receptor through an enhancer sequence at -954 base pairs. c-Fos and c-Jun bound the cyclin D1 -954 enhancer sequence, and the abundance of c-Fos within this complex was increased by AII treatment. AII induced extracellular signal-regulated kinase (ERK) activity 7-fold, and dominant-negative mutants of either p21(ras) or ERK reduced AII-stimulated cyclin D1 promoter activity. These findings suggest that AII may stimulate mitogenesis by increasing CD1K activity through a p21(ras)/ERK/activator protein 1 pathway.
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PMID:Angiotensin II activation of cyclin D1-dependent kinase activity. 879 25

The c-fos promoter is negatively regulated by the retinoblastoma (Rb)-susceptibility-gene-encoded protein as well as by other genes involved in the control of transcription, cell cycle regulation and neoplastic transformation. We have examined by immunohistochemistry the c-Fos and c-Jun proteins in five cases of retinoblastoma in order to evaluate eventual alterations in their expression in vivo, possibly related to a gene mutation or to loss of Rb negative control.
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PMID:Immunohistochemical analysis of c-Fos and c-Jun in retinoblastoma. 887 49

p202, an interferon-inducible murine protein, is a member of the "200 family" of proteins and is primarily nuclear. p202 is a modulator of transcription; it binds several transcription factors, including NF-kappaB p50 and p65, AP-1 c-Fos and c-Jun, and E2F1, and inhibits their transcriptional activity. p202 also binds pRb, the retinoblastoma protein, and if overexpressed it retards cell proliferation. Here we report that using the yeast two-hybrid assay we found that p202 bound the murine homolog of the human p53-binding protein 1 (53BP1), a protein shown to interact with the DNA binding domain of the p53 tumor suppressor protein. p202 bound a 98amino acid segment from 53BP1. This binding was inhibited by the replacement in p202 of a histidine (from the M(F/L)HATVA(T/S) sequence that is conserved among all of the 200 family proteins) by phenylalanine. We also report that overexpression of p202 inhibited the p53-dependent expression of reporter genes containing p53-activable segments from the mdm2 and p21 genes, whereas a decrease in the p202 level (in consequence of the expression of 202 antisense RNA) resulted in an increase in the p53-dependent expression of these reporters. Expression of the 53BP1 segment binding to p202 overcame the inhibition by overexpressed p202 of the transcription of reporters mediated by the p53 or the AP-1 transcription factors and of the proliferation of yeast.
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PMID:p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. 891 Mar 40


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