Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The tyrosine kinase inhibitor (tyrphostin) AG 555 selectively interferes with viral transcription in bovine papillomavirus type 1 (BPV-1)-transformed fibroblasts and induces suppression of cyclin-dependent kinase activity and cell cycle arrest. Concomitant with inhibition of viral transcription, c-Jun was strongly up-regulated, which was consistent with the observation that AG 555 treatment also led to an activation of the mitogen-activated protein kinase pathway by enhancing phosphorylation of JNK and p38. Increased JNK and p38 activity resulted in higher phosphorylation of the AP-1 family members c-Jun and activating transcription factor 2. Scanning the BPV-1 genome for potential binding sequences, an intragenic AP-1 site (BAP-1) within the E7 open reading frame was detected. Enhanced dimerization of phosphorylated activating transcription factor 2 together with c-Jun and binding to BAP-1 seem to be responsible for viral dysregulation because both suppression of BPV-1 and induction of c-Jun mRNA could be almost entirely abrogated by simultaneous treatment with SB 203580, an inhibitor of p38 mitogen-activated protein kinase activity. Moreover, dissecting the complex transcriptional pattern of episomal BPV-1 with specific primer sets for reverse transcription-PCR analysis, the repressive effect could be attributed to a selective down-regulation of the mRNA encoding the E2 transactivator function in favor of the E2 repressor, whose mRNA level remained constant during AG 555 treatment. These data indicate that tyrphostin AG 555 disturbs the balance of negative and positive regulatory factors necessary to maintain the homeostasis of a virus-transformed phenotype.
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PMID:Tyrphostin AG 555 inhibits bovine papillomavirus transcription by changing the ratio between E2 transactivator/repressor function. 1286 21

p18(INK4c), a member of INK4 family of cyclin-dependent kinase inhibitors, negatively regulates the cyclin D-cyclin-dependent kinase 4/6 complexes which promote G1/S transition by phosphorylating the retinoblastoma tumor-suppressor gene product. Several recent studies using p18(INK4c)-null mice revealed that the p18(INK4c) plays an important role in cell proliferation and tumor development. We report here that 12-O-tetradecanoylphorbol-13-acetate (TPA), widely used as a protein kinase C (PKC) activator, suppresses the expression of p18(INK4c) through its promoter, accompanied by the induction of human cancer cell growth. Reduction of p18(INK4c) using small interfering RNA (siRNA) also enhanced cell growth, suggesting that p18(INK4c) is a critical target of TPA. Ro 31-8425, a potent and highly specific PKC inhibitor abrogated the suppressive effect of TPA on p18(INK4c) gene expression. However, the expression of dominant-negative c-Jun (TAM-67) did not inhibit the action of TPA on p18(INK4c). These findings suggest that activation of PKC promotes human cancer cell growth through downregulation of p18(INK4c) in an AP-1 activation-independent manner. These results suggest that the accelerated cellular proliferation of some human tumors caused by enhanced PKC activity at least partially involves the suppression of p18(INK4c), which is a ubiquitously expressed cyclin-dependent kinase inhibitor.
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PMID:Activation of protein kinase C promotes human cancer cell growth through downregulation of p18(INK4c). 1510 19

It is well known that the cell cycle is controlled by several cyclin/cyclin-dependent kinase (Cdk) complexes whose expression and phosphorylation states vary with orderly periodicity. During the cell cycle, activity of the cyclin/Cdk complexes can be regulated directly or indirectly by a number of molecules, including protein kinases and phosphatases, p53, and Cdk inhibitors. Here, we show that the addition of glial cell line-derived neurotrophic factor (GDNF) induced G2/M cell cycle delay in human SK-N-MC neuroectodermal tumor cells that express RET tyrosine kinase, accompanying actin reorganization. Cell cycle delay at G2/M was characterized by accelerated and prolonged Cdc2 phosphorylation and stabilization of cyclin B1 and Wee1 kinase expression. Interestingly, we found that phosphorylation and/or expression of Cdc2, cyclinB1, and Wee1 was controlled by the Rac1/c-Jun NH2-terminal kinase (JNK) pathway. Immunohistochemical analysis suggested that the G2/M cell cycle delay may be necessary to prevent the mitotic progression of SK-N-MC cells with perturbed actin cytoskeletons.
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PMID:Activation of c-Jun amino-terminal kinase by GDNF induces G2/M cell cycle delay linked with actin reorganization. 1596 97

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found in grapes, and has been shown to inhibit the growth of various types of cancer cells. We investigated the mechanism of the antiproliferative effect of resveratrol in A431-transformed keratinocytes harbouring mutant p53, and show that it is accompanied by G1 cell cycle arrest, which coincides with a marked inhibition of G1 cell cycle regulatory proteins, including cyclins A and D1 and cyclin-dependent kinase (CDK)6 and p53-independent induction of p21WAF1. Cell cycle arrest was also associated with the accumulation of hypophosphorylated Rb and p27KIP1. Resveratrol inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 > extracellular signal-regulated protein kinase (ERK)1/2 signalling, downregulated c-Jun, and suppressed activating protein (AP)-1 DNA-binding and promoter activity. In addition, the inhibition of MEK1 > ERK1/2 signalling appears to be independent of retinoblastoma protein (pRb) hypophosphorylation in A431 cells, as PD098059 did not suppress pRb phosphorylation. Our results demonstrate that resveratrol affects multiple cellular targets in A431 cells, and that the downregulation of both AP-1 and pRb contributes to its antiproliferative activity in these cells.
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PMID:Resveratrol inhibits proliferation of human epidermoid carcinoma A431 cells by modulating MEK1 and AP-1 signalling pathways. 1676 63

Hippocampal kindling, a model of mesial temporal lobe epilepsy, is developed through repetitive stimulation of the hippocampus and leads to increased after-discharges as measured by EEG and an enduring seizure-prone state. Synthesis of new proteins is thought to form the basis for sustained seizure-induced physiological and/or pathological changes in synaptic reorganization and apoptotic/necrotic neuronal death. Here we examined the effect of kindling on stimulus-induced c-Jun N-terminal kinase (JNK) and p38 phosphorylation, events postulated to lie upstream of seizure-induced changes in gene transcription. We found that stimulus-induced phosphorylation of JNK, but not of p38, is significantly enhanced in kindled animals compared with their naive counterparts in the CA1 subregion of the hippocampus. Immunofluorescent staining confirmed this region-specific pattern of JNK activation and revealed that reactive astrocytes mediate this effect. Astrocyte proliferation and hypertrophy, as well as upregulation of vimentin protein levels, common markers of astrogliosis, were present after 4 d of kindling. Moreover, this reactive astrogliosis was associated with neuronal death as visualized with Fluoro-jade B and anti-active caspase-3 staining. Stimulus-induced phosphorylation of the JNK substrate paxillin was enhanced in kindled animals, but not that of c-Jun. Moreover, a pan-antibody against MAPK/CDK (mitogen-activated protein kinases/cyclin-dependent kinase) substrates indicated the presence of phosphorylated proteins in cytosolic, membrane, and nuclear fractions. The consequence of these phosphorylation events is not completely understood, but these findings suggest a selective astrocytic signaling response to aberrant synaptic activity, signaling that may modulate kindling progression and/or neuronal death.
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PMID:c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes. 1689 24

In this study, we investigated the anticancer effect of protoapigenone on human prostate cancer cells. Protoapigenone inhibited cell growth through arresting cancer cells at S and G(2)/M phases as well as inducing apoptosis. Blockade of cell cycle by protoapigenone was associated with an increase in the levels of inactivated phospho (p)-Cdc25C (Ser216) and a decrease in the levels of activated p-cyclin B1 (Ser147), cyclin B1, and cyclin-dependent kinase (Cdk) 2. Protoapigenone triggered apoptosis by increasing the levels of cleaved poly(ADP-ribose) polymerase and caspase-3. In addition, activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK)1/2 was a critical mediator in protoapigenone-induced cell death. Inhibition of the expression of p38 MAPK and JNK1/2 by pharmacological inhibitors or specific small interfering RNA reversed the protoapigenone-induced apoptosis through decreasing the level of cleaved caspase-3. In contrast, p38 MAPK, but not JNK1/2, was involved in the protoapigenone-mediated S and G(2)/M arrest by modulating the levels of Cdk2 and p-Cdc25C (Ser216). Moreover, in vivo xenograft study showed that protoapigenone had a significant inhibition of prostate tumor growth without major side effects on the mice we tested. This inhibition was associated with induction of apoptosis and activation of p38 MAPK and JNK1/2 in protoapigenone-treated tumor tissues. In conclusion, our results demonstrated protoapigenone suppressed prostate cancer cell growth through the activation of p38 MAPK and JNK1/2, with the potential to be developed as a chemotherapeutic agent for prostate cancer.
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PMID:Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2. 1833 75

Activation of the double-stranded RNA-dependent protein kinase (PKR) has been implicated in the pathogenesis of several neurodegenerative diseases. We find that a compound widely used as a pharmacological inhibitor of this enzyme, referred to as PKR inhibitor (PKRi), {8-(imidazol-4-ylmethylene)-6H-azolidino[5,4-g]benzothiazol-7-one}, protects against the death of cultured cerebellar granule and cortical neurons. PKRi also prevents striatal neurodegeneration and improves behavioral outcomes in a chemically induced mouse model of Huntington's disease. Surprisingly, PKRi fails to block the phosphorylation of eIF2alpha, a downstream target of PKR, and does not reduce the autophosphorylation of PKR enzyme immunoprecipitated from neurons. Furthermore, neurons lacking PKR are fully protected from apoptosis by PKRi, demonstrating that neuroprotection by this compound is not mediated by PKR inhibition. Using in vitro kinase assays we investigated whether PKRi affects any other protein kinase. These analyses demonstrated that PKRi has no major inhibitory effect on pro-apoptotic kinases such as the c-Jun N-terminal kinases, the p38 MAP kinases and the death-associated protein kinases, or on other kinases including c-Raf, MEK1, MKK6 and MKK7. PKRi does, however, inhibit the activity of certain cyclin-dependent kinases (CDKs), including CDK1, CDK2 and CDK5 both in vitro and in low potassium-treated neurons. Consistent with its inhibitory action on mitotic CDKs, the treatment of HT-22 and HEK293T cell lines with PKRi sharply reduces the rate of cell cycle progression. Taken together with the established role of CDK activation in the promotion of neurodegeneration, our results suggest that PKRi exerts its neuroprotective action by inhibiting CDK.
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PMID:A chemical compound commonly used to inhibit PKR, {8-(imidazol-4-ylmethylene)-6H-azolidino[5,4-g] benzothiazol-7-one}, protects neurons by inhibiting cyclin-dependent kinase. 1904 82

c-Jun is a component of the activator protein-1 (AP-1) complex, which plays a crucial role in the regulation of gene expression, cell proliferation, and cell transformation, as well as cancer development. Herein, we found that cyclin-dependent kinase (Cdk)-3, but not Cdk2 or c-Jun NH(2)-terminal kinase, is a novel kinase of c-Jun induced by stimulation with growth factors such as epidermal growth factor (EGF). Cdk3 was shown to phosphorylate c-Jun at Ser63 and Ser73 in vitro and ex vivo. EGF-induced Cdk3 activation caused c-Jun phosphorylation at Ser63 and Ser73, resulting in increased AP-1 transactivation. Ectopic expression of Cdk3 resulted in anchorage-independent cell transformation of JB6 Cl41 cells induced by EGF and foci formation stimulated by constitutively active Ras (Ras(G12V)), which was mediated by AP-1 in NIH3T3 cells. These results showed that the Cdk3/c-Jun signaling axis plays an important role in EGF-stimulated cell proliferation and cell transformation.
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PMID:Cyclin-dependent kinase-3-mediated c-Jun phosphorylation at Ser63 and Ser73 enhances cell transformation. 1911 12

Transforming growth factor (TGF)-beta initially inhibits growth of mature epithelial cells. Later, however, autocrine TGF-beta signaling acts in concert with the Ras pathway to induce a proliferative and invasive phenotype. TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also Ras-associated kinases, which differentially phosphorylate the mediators Smad2 and Smad3 to create distinct phosphorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C) and both linker and COOH-terminally phosphorylated Smad2/3 (pSmad2L/C and pSmad3L/C). In this study, we investigated actions of pSmad2L/C and pSmad3L/C in cancer progression. TGF-beta inhibited cell growth by down-regulating c-Myc oncoprotein through the pSmad2C and pSmad3C pathway; TGF-beta signaling, in turn, enhanced cell growth by up-regulating c-Myc through the cyclin-dependent kinase (CDK) 4-dependent pSmad2L/C and pSmad3L/C pathways in cell nuclei. Alternatively, TbetaRI and c-Jun NH2-terminal kinase (JNK) together created cytoplasmic pSmad2L/C, which entered the nucleus and stimulated cell invasion, partly by up-regulating matrix metalloproteinase-9. In 20 clinical samples, pSmad2L/C and pSmad3L/C showed nuclear localization at invasion fronts of all TGF-beta-producing human metastatic colorectal cancers. In vitro kinase assay confirmed that nuclear CDK4 and cytoplasmic JNK obtained from the tumor tissue could phosphorylate Smad2 or Smad3 at their linker regions. We suggest that CDK4, together with JNK, alters tumor-suppressive TGF-beta signaling to malignant characteristics in later stages of human colorectal cancer. The linker phosphorylation of Smad2 and Smad3 may represent a target for intervention in human metastatic cancer.
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PMID:Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGF-beta signal in later stages of human colorectal cancer. 1953 54

In inflammatory diseases, tissue damage is critically associated with nitric oxide ((*)NO) and cytokines, which are overproduced in response to cellular release of endotoxins. Here we investigated the inhibitory effect of roscovitine, a selective inhibitor of cyclin-dependent kinases (CDKs) on (*)NO production in mouse macrophages. In RAW264.7 cells, we found that roscovitine abolished the production of (*)NO induced by lipopolysaccharide (LPS). Moreover, roscovitine significantly inhibited LPS-induced inducible nitric oxide synthase (iNOS) mRNA and protein expression. Our data also showed that roscovitine attenuated LPS-induced phosphorylation of IkappaB kinase beta (IKKbeta), IkappaB, and p65 but enhanced the phosphorylation of ERK, p38, and c-Jun NH(2)-terminal kinase (JNK). In addition, roscovitine dose dependently inhibited LPS-induced expression of cyclooxygenase-2 (COX)-2, IL-1beta, and IL-6 but not tumor necrosis factor (TNF)-alpha. Tetrahydrobiopterin (BH(4)), an essential cofactor for iNOS, is easily oxidized to 7,8-dihydrobiopterin (BH(2)). Roscovitine significantly inhibited LPS-induced BH(4) biosynthesis and decreased BH(4)-to-BH(2) ratio. Furthermore, roscovitine greatly reduced the upregulation of GTP cyclohydrolase-1 (GCH-1), the rate-limiting enzyme for BH(4) biosynthesis. Using other CDK inhibitors, we found that CDK1, CDK5, and CDK7, but not CDK2, significantly inhibited LPS-induced (*)NO production in macrophages. Similarly, in isolated peritoneal macrophages, roscovitine strongly inhibited (*)NO production, iNOS, and COX-2 upregulation, activation of NFkappaB, and induction of GCH-1 by LPS. Together, our data indicate that roscovitine abolishes LPS-induced (*)NO production in macrophages by suppressing nuclear factor-kappaB activation and BH(4) biosynthesis, which might be mediated by CDK1, CDK5, and CDK7. Our results also suggest that roscovitine may inhibit inflammation and that CDKs may play important roles in the mechanisms by which roscovitine attenuates inflammation.
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PMID:Inhibition of CDKS by roscovitine suppressed LPS-induced *NO production through inhibiting NFkappaB activation and BH4 biosynthesis in macrophages. 1955 66


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