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)

A new type of peroxiredoxin, named 1-Cys peroxiredoxin (1-Cys Prx), reduces hydrogen peroxide with the use of electrons from unidentified electron donor(s). We have isolated the mouse gene encoding 1-Cys Prx (CP-3) and shown that it is comprised of five exons and four introns. Analysis of 5' flanking regions revealed binding sequences of several putative transcription factors such as Sp1, Pit-1a, c-Jun, c-Myc and YY1. It is noticeable that several potential Sp1 binding sites assigned the -60 through -96bp from putative transcription initiation site. The gel shift assays showed that Sp1 and Pit-1a bind specifically to each binding site in 1-Cys Prx promoter. We also isolated two highly related genes such as CP-2 and CP-5. These genes are encoded by single exons, and show 85% of nucleotide sequence homology with the CP-3. The structural features of these genes suggest that they might be intronless genes derived from the CP-3 by the mechanism involving retrotransposition. In addition, our data suggest that they are inserted to a specific site of the mouse L1 repetitive element. The 1-Cys Prx was actively transcribed in a variety of adult tissues as well as in the developing embryos. These results suggest that only the 1-Cys Prx gene might be relevant for studying the function of the 1-Cys Prx in the murine system.
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PMID:Characterization of the murine gene encoding 1-Cys peroxiredoxin and identification of highly homologous genes. 1039 7

The role of two vertebrate mitogen-activated protein kinases (MAPKs) in mediating responses to in vivo anoxia or freezing exposures was examined in four organs (liver, heart, kidney and brain) of hatchling red-eared turtles, Trachemys scripta elegans, which are naturally tolerant of these stresses. The extracellular signal-regulated kinases were not stress-activated except in brain of frozen turtles. The c-Jun NH2-terminal kinases (JNKs) were transiently activated by anoxia exposure in all four organs (after 1 h in brain or 5 h in other organs) but activity was suppressed during freezing except in brain which showed a transient activation of JNK after 1 h. Changes in the concentrations of the transcription factors, c-Fos and c-Myc, were also stress- and organ-specific. The patterns of MAPK activation in a stress-tolerant animal suggest the relative importance of these kinase pathways in cellular adaptation to oxygen deprivation or freezing and identify novel natural activators of MAPKs in vivo. The specificity of the signaling pathways is also emphasized here as the general whole-body stresses, anoxia and freezing, activated individual MAPKs in a tissue-, time-, and stress-dependent manner.
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PMID:Discordant responses of mitogen-activated protein kinases to anoxia and freezing exposures in hatchling turtles. 1059 22

Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.
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PMID:Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. 1059 2

Crocetin, a major component of the fruit of Gardenia jasminoides Ellis, was investigated for its antitumor promoting effect on 12-O-tetradecanoylphorbol-13-acetate-promoted mouse skin carcinogenesis. Topical application of 5 nmol TPA to CD-1 mice once daily for 5 days caused epidermal hyperplasia, and increases in the levels of c-Fos, c-Jun and c-Myc in the suprabasal layer of epidermis and the muscle layer of dermis. Immunocytolochemical examination showed that pretreatment of 1 mumol crocetin repressed the TPA-induced epidermal hyperplasia and the expressions of c-Jun, c-Fos and c-Myc to the extent of 47, 44 and 45% respectively. Crocetin of 3.0 mumol exhibited stronger inhibition on the induced hyperplasia and the oncoproteins levels (by 60, 53 and 55% respectively). Western blotting analysis confirmed this inhibitory effect of crocetin. Pretreatment of crocetin also repressed the TPA-induced H2O2 production and myeloperoxidase activity. These data indicate that crocetin suppresses the TPA-induced skin carcinogenesis maybe via its antioxidant property which, in turn, leads to a reduction in the TPA-induced expressions of c-Jun, c-Fos and c-Myc in mouse epidermis.
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PMID:Suppression of the TPA-induced expression of nuclear-protooncogenes in mouse epidermis by crocetin via antioxidant activity. 1062 78

The transforming growth factor beta (TGF-beta) plays an important role in constraining cellular proliferation, but it is also a potent inducer of programmed cell death or apoptosis. Here, we demonstrate that TGF-beta can have an opposite effect, acting as a survival factor to prevent c-Myc-induced cell death in Rat-1 fibroblasts. However, in marked contrast to TGF-beta, Smad2, which is a critical intracellular mediator of the TGF-beta signaling pathway, functions as an antagonist to induce increased cell death. The protective activity of TGF-beta was associated with the activation of c-Jun N-terminal Kinase (JNK) and was not linked to the ability of TGF-beta to promote cell cycle progression. Expression of dominant-interfering forms of various components of the JNK signaling pathway, including Rac1, Cdc42, mitogen-activated protein kinase kinase 4 (MKK4), and c-Jun, abolished TGF-beta-mediated cell survival. Furthermore, overexpression of the constitutively activated mutant RacL61F37A, which selectively stimulates JNK cascade but not G1 cell cycle progression or actin polymerization, was sufficient to prevent apoptosis induced by c-Myc. These findings describe a differential effect of two separated signaling pathways of TGF-beta and indicate for the first time that Smad2 can act as antagonist to suppress TGF-beta-dependent cell survival. Oncogene (2000) 19, 1277 - 1287.
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PMID:Differential roles of JNK and Smad2 signaling pathways in the inhibition of c-Myc-induced cell death by TGF-beta. 1071 69

Ku is a heterodimeric protein composed of approximately 70- and approximately 80-kDa subunits (Ku70 and Ku80) originally identified as an autoantigen recognized by the sera of patients with autoimmune diseases. Ku has high binding affinity for DNA ends and that is why originally it was known as a DNA end binding protein, but now it is known to also bind the DNA structure at nicks, gaps, hairpins, as well as the ends of telomeres. It has been reported also to bind with sequence specificity to DNA and with weak affinity to RNA. Ku is an abundant nuclear protein and is present in vertebrates, insects, yeast, and worms. Ku contains ssDNA-dependent ATPase and ATP-dependent DNA helicase activities. It is the regulatory subunit of the DNA-dependent protein kinase that phosphorylates many proteins, including SV-40 large T antigen, p53, RNA-polymerase II, RP-A, topoisomerases, hsp90, and many transcription factors such as c-Jun, c-Fos, oct-1, sp-1, c-Myc, TFIID, and many more. It seems to be a multifunctional protein that has been implicated to be involved directly or indirectly in many important cellular metabolic processes such as DNA double-strand break repair, V(D)J recombination of immunoglobulins and T-cell receptor genes, immunoglobulin isotype switching, DNA replication, transcription regulation, regulation of heat shock-induced responses, regulation of the precise structure of telomeric termini, and it also plays a novel role in G2 and M phases of the cell cycle. The mechanism underlying the regulation of all the diverse functions of Ku is still obscure.
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PMID:Ku autoantigen: a multifunctional DNA-binding protein. 1075 64

The aldosterone-induced increase in sodium reabsorption across tight epithelia can be divided schematically into two functional phases: an early regulatory phase starting after a lag period of 20 to 60 minutes, during which the pre-existing transport machinery is activated, and a late phase (>2.5 h), which can be viewed as an anabolic action leading to a further amplification/differentiation of the Na+ transport machinery. At the transcriptional level, both early and late responses are initiated during the lag period, but the functional impact of newly synthesized regulatory proteins is faster than that of the structural ones. K-Ras2 and SGK were identified as the first early aldosterone-induced regulatory proteins in A6 epithelia. Their mRNAs also were shown to be regulated in vivo by aldosterone, and their expression (constitutively active K-Ras2 and wild-type SGK) was shown to increase the function of ENaC coexpressed in Xenopus oocytes. Recently, aldosterone was also shown to act on transcription factors in A6 epithelia: It down-regulates the mRNAs of the proliferation-promoting c-Myc, c-Jun, and c-Fos by a post-transcriptional mechanism, whereas it up-regulates that of Fra-2 (c-Fos antagonist) at the transcriptional level. Together, these new data illustrate the complexity of the regulatory network controlled by aldosterone and support the view that its early action is mediated by the induction of key regulatory proteins such as K-Ras2 and SGK. These early induced proteins are sites of convergence for different regulatory inputs, and thus, their aldosterone-regulated expression level tunes the impact of other regulatory cascades on sodium transport. This suggests mechanisms for the escape from aldosterone action.
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PMID:Pleiotropic action of aldosterone in epithelia mediated by transcription and post-transcription mechanisms. 1076 54

Apoptosis has been well established as a vital biological phenomenon that is important in the maintenance of cellular homeostasis. Three major protooncogene families and their encoded proteins function as mediators of apoptosis in various cell types and are the subject of this chapter. Protooncogenic proteins such as c-Myc/Max, c-Fos/c-Jun, and Bcl-2/Bax utilize a synergetic effect to enhance their roles in the pro- or antiapoptotic action. These family members activate and repress the expression of their target genes, control cell cycle progression, and execute programmed cell death. Repression or overproduction of these protooncogenic proteins induces apoptosis, which may vary as a result of either cell type specificity or the nature of the apoptotic stimuli. The proapoptotic and antiapoptotic proteins exert their effects in the membrane of cellular organelles. Here they generate cell-type-specific signals that activate the caspase family of proteases and their regulators for the execution of apoptosis.
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PMID:Protooncogenes as mediators of apoptosis. 1076 Nov 17

Src-like adapter protein (Slap) is a recently identified protein that negatively regulates mitogenesis in murine fibroblasts (S. Roche, G. Alonso, A. Kazlausakas, V. M. Dixit, S. A. Courtneidge, and A. Pandey, Curr. Biol. 8:975-978, 1998) and comprises an SH3 and SH2 domain with striking identity to the corresponding Src domains. In light of this, we sought to investigate whether Slap could be an antagonist of all Src functions. Like Src, Slap was found to be myristylated in vivo and largely colocalized with Src when coexpressed in Cos7 cells. Microinjection of a Slap-expressing construct into quiescent NIH 3T3 cells inhibited platelet-derived growth factor (PDGF)-induced DNA synthesis, and the inhibition was rescued by the transcription factor c-Myc but not by c-Jun/c-Fos expression. Fyn (or Src) overexpression overrides the G(1)/S block induced by both SrcK- and a Slap mutant with a deletion of its C terminus (SlapDeltaC), but not the block induced by Slap or SlapDeltaSH3, implying that the C terminus is a noncompetitive inhibitor of Src mitogenic function. Furthermore, a chimeric adapter comprising SrcDeltaK fused to the Slap C terminus (Src/SlapC) also inhibited Src function during the PDGF response in a noncompetitive manner, as Src coexpression could not rescue PDGF signaling. Slap, however, did not reverse deregulated Src-induced cell transformation, as it was unable to inhibit depolymerization of actin stress fibers while still being able to inhibit SrcY527F-induced DNA synthesis. This was attributed to a distinct Slap SH3 binding specificity, since the chimeric Slap/SrcSH3 molecule, in which the Slap SH3 was replaced by the Src SH3 sequence, substantially restored stress fiber formation. Indeed, three amino acids important for ligand binding in Src SH3 were replaced in the Slap SH3 sequence; Slap SH3 did not bind to the Src SH3 partners p85alpha, Shc, and Sam68 in vitro, and the chimeric tyrosine kinase Slap/SrcK, composed of SlapDeltaC fused to the SH2 linker kinase sequence of Src, was not regulated in vivo. Furthermore, the Src SH3 domain is required for signaling during mitogenesis and since Slap/SrcK behaved as a dominant negative in the PDGF mitogenic response when microinjected into quiescent fibroblasts. We conclude that Slap is a negative regulator of Src during mitogenesis involving both the SH2 and the C terminus domains in a noncompetitive manner, but it does not regulate all Src function due to specific SH3 binding substrates.
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PMID:Slap negatively regulates Src mitogenic function but does not revert Src-induced cell morphology changes. 1077 29

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by hyperplasia of the synovial lining cells, angiogenesis, and infiltration of mononuclear cells resulting in pannus formation, cartilage erosion and ultimately joint destruction. Synovial tissue (ST) fibroblast hyperplasia is reminiscent of tumor-like proliferation and is a major cause of cartilage destruction in the RA joint. The RA joint is replete with cytokines and growth factors which exert a synergistic mitogenic effect on ST fibroblasts. As a result, RA ST fibroblasts exhibit elevated gene expression of proto- oncogenes, such as c-Myc, c-Ras, and c-Jun and apoptosis inhibitors such as Bcl-2. At the same time, RA ST fibroblasts contain mutations in tumor suppressor genes such as p53. The altered rates of proliferation and apoptosis of RA synovial cells result in the hyperplasia of synovial tissue and in concert with the chronic inflammatory environment ultimately lead to the destruction of the RA joint.
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PMID:Cell cycle implications in the pathogenesis of rheumatoid arthritis. 1083 66


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