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)

Transitions from small cell (SCLC) to non-small cell lung cancer (NSCLC) cells have been documented both in vitro and in vivo and are thought to be an important step during tumor progression of human small cell lung cancer towards a treatment-resistant tumor state. We have screened NSCLC and SCLC cell lines for differences in the composition of nuclear transcription factors using consensus oligonucleotide sequences (SRE, Ets, TRE, CRE, B-motif, GAS, E-box). We found NSCLC cells to exhibit significantly higher AP-1 binding activity than SCLC cells consistent with the increased expression of CD44, an AP-1 target gene. To gain more insight into the molecular mechanisms underlying these differences, we analysed SCLC cell lines (NCI-N592 and NCI-H69) which were phenotypically transformed into NSCLC-type cells by transfection with activated H-ras and c-myc oncogenes. In these cells, ras-induced transition is accompanied by a strong induction of AP-1-binding activity along with increased expression of CD44 mRNA and protein. When analysing the composition of the AP-1 complex in more detail and comparing ras-induced versus phorbol ester-induced changes, we found Fra-1 to be the major component induced in ras-transfected but not in phorbol-ester treated or non-treated parental SCLC cells. This finding is paralleled by the observation that among the various members of the Fos and Jun family analysed (c-Fos, FosB, Fra-1, Fra-2, c-Jun, JunD, JunB) fra-1 is the only gene to be exclusively expressed in NSCLC cells but not in cells of SCLC origin. Our data, thus, point to a histiotype-related mechanism of recruitment among AP-1 proteins which may have bearings on the fate of lung cancer development.
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PMID:Transition from SCLC to NSCLC phenotype is accompanied by an increased TRE-binding activity and recruitment of specific AP-1 proteins. 966 39

Activating mutations in ras genes are frequently associated with non-small cell lung cancer cells (NSCLC) and contribute to transformed growth in these cells. Expression of oncogenic forms of Ras in these cells is associated with increased expression and activity of cytosolic phospholipase A(2) (cPLA(2)) and cyclooxygenase-2 (COX-2), leading to constitutively elevated levels of prostaglandin production. Expression of oncogenic Ras is sufficient to induce these enzymes in normal lung epithelial cells. We have previously reported that the JNK and ERK pathways are necessary for induction of cPLA(2) and have defined a minimal region of the cPLA(2) promoter from -58 to -12 that is required for Ha-Ras-mediated induction. To further characterize the cis-regulatory elements within this region involved in this response, site-directed mutagenesis was used to make mutations at various sites. Three cis-regulatory elements were identified: regions -21/-18, -37/-30, and -55/-53. Mutations in any of these elements decreased basal and Ha-Ras-induced cPLA(2) promoter activity in both normal lung epithelial cells, as well as steady state promoter activity in A549 cells, with a mutation in element -21/-18 completely eliminating all promoter activity. Overexpression studies and gel shift assays indicated that Sp1 may serve as a transcription factor functionally regulating promoter activity by directly interacting with two of the cis-regulatory elements, -21/-18 and -37/-30. Expression of Ha-Ras led to induction of c-Jun protein, which showed functional cooperation with Sp1 in driving promoter activity. Additional unidentified transcription factors bound to the regions from -55/-53 and -37/-34.
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PMID:Induction of cPLA2 in lung epithelial cells and non-small cell lung cancer is mediated by Sp1 and c-Jun. 1155 11

All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of G(alphaq) and G(alpha12,13). Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting G(alphaq) and stimulating G(alpha12,13). However, these SPDs had low potency and short half-lives. In this report we show that a bradykinin antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric bradykinin antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two antagonists. CU201 inhibited intracellular Ca2+ release in response to bradykinin, indicating blockage of the G(alphaq) signal, and stimulated c-Jun kinases, indicating stimulation of the G(alpha12,13) pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties.
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PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a "biased agonist" mechanism. 1193 11

Adrenomedullin (AM) is a hypotensive polypeptide that has been shown to stimulate cyclic AMP and intracellular free Ca2+ agents that are known to induce expression of proto-oncogenes, in various cell types. Transforming growth factor-beta 1 (TGF-beta1) is a multifunctional polypeptide that regulates proliferation, differentiation and cell cycle progression in both normal and malignant epithelial cells. The diverse biological actions of AM and TGF-beta1 may be related to their capacities to initiate different genomic programs in target cells via the induction of expression of multiple genes including early response genes and proto-oncogenes. AM, TGF-beta1 and phorbol-12-myristate-13-acetate (PMA) exert both positive and negative effects on mitogenesis. The effects of AM, TGF-beta1 and PMA were examined in human non-small cell lung cancer (NSCLC) cells. AM caused an increase in its mRNA transcript that peaked by 6 hours and persisted to 24 hours. While expression of TGF-beta1 mRNA was not affected by AM in these cells, the mRNAs for TGF-beta1 and TGF-beta3 decreased by 3 hours. In contrast, TGF-beta1 had no effect on expression of AM mRNA. Interestingly, PMA caused an increase in AM and TGF-beta1 mRNAs in NSCLC cells. While both TGF-beta1 and PMA caused a transient increase in expression of the mRNAs for early response genes including c-fos, c-jun and egr-1 that peaked by 1 hour following treatment, the increase in expression of these mRNAs following treatment with AM peaked only after 3-6 hours. Western blotting analysis showed increases in the levels of c-jun protein following treatment with AM, TGF-beta1 and PMA. The increase in c-jun protein from treatment with AM occurred 10 hours after that from TGF-beta1 and PMA. Activator protein 1 (AP-1) DNA binding activity was also demonstrated to increase following treatment with AM, TGF-beta1 and PMA, with the increase in AP-1 DNA binding activity following AM treatment occurring 10 hours later than that from TGF-beta1 and PMA treatment. These data show that AM can regulate expression of its mRNA transcript in NSCLC cells. Our study suggests that NSCLC cells are important targets of AM and TGF-beta1 and that AM and TGF-beta1 may regulate activities in these malignant lung cells through differential induction of various early response genes.
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PMID:Differential induction of early response genes by adrenomedullin and transforming growth factor-beta1 in human lung cancer cells. 1216 20

We examined the ability of adenoviral-mediated expression of the melanoma differentiation associated gene-7 (Ad-mda-7), to radiosensitize non-small cell lung cancer (NSCLC) cell lines (A549 (wt-TP53/wt-RB1) and H1299 (del-TP53/wt-RB1)), and normal human lung fibroblast (NHLF) lines (CCD-16 and MRC-9). Results of clonogenic assays indicated that Ad-mda7 enhanced the radiosensitivity of the NSCLC cells independent of their TP53 gene status. On the other hand, the NHLF cell lines seemed to be relatively resistant to the cytotoxic effects of Ad-mda7 and were not radiosensitized compared with the NSCLC cells. We further examined the basis for this difference in the ability of Ad-mda7 to radiosensitize NSCLC cells compared with normal cells. Radiation-induced apoptosis was restored in the NSCLC lines, but not in the normal lines. Western blot analysis revealed that Ad-mda7 enhances radiosensitivity independently of any ability to upregulate the expression of Fas or Bax in NSCLC cells. Further analysis indicated that phosphorylated c-Jun expression was increased by Ad-mda7 in both A549 and H1299 cells, but not in CCD-16 cells. These results support the use of gene replacement with Ad-mda7 in combination with radiotherapy for the treatment of NSCLC.
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PMID:Adenovirus-mediated mda-7 gene expression radiosensitizes non-small cell lung cancer cells via TP53-independent mechanisms. 1240 62

Protein kinase D (PKD) has been established as a negative modulator of the c-Jun N-terminal kinase (JNK) signaling pathway. We previously demonstrated that induced expression of constitutively active PKD (PKD-S744/748E) that mimics phosphorylation by PKC is sufficient to attenuate epidermal growth factor (EGF) stimulated c-Jun Ser 63 phosphorylation, a natural substrate of JNK, in HEK 293 cells. Because the JNK pathway has been implicated in sustaining both lung and pancreatic cancerous phenotypes, we have utilized stable inducible expression of PKD-S744/748E in clones of A549 non-small cell lung cancer (NSCLC) and Panc1, pancreatic cancer cells to determine its effects on JNK signaling in the context of the cancerous phenotype. In contrast to HEK 293 cells, induced expression of PKD-S744/748E in either A549 NSCLC or Panc1 cells failed to attenuate EGF dependent phosphorylation of c-Jun, indicating that EGF stimulated JNK phosphorylation of c-Jun is uncoupled from PKD suppression in these cancer cells.
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PMID:Uncoupling of protein kinase D from suppression of EGF-dependent c-Jun phosphorylation in cancer cells. 1264 40

Cancer cells in which the PTEN lipid phosphatase gene is deleted have constitutively activated phosphatidylinositol 3-kinase (PI3K)-dependent signaling and require activation of this pathway for survival. In non-small cell lung cancer (NSCLC) cells, PI3K-dependent signaling is typically activated through mechanisms other than PTEN gene loss. The role of PI3K in the survival of cancer cells that express wild-type PTEN has not been defined. Here we provide evidence that H1299 NSCLC cells, which express wild-type PTEN, underwent proliferative arrest following treatment with an inhibitor of all isoforms of class I PI3K catalytic activity (LY294002) or overexpression of the PTEN lipid phosphatase. In contrast, overexpression of a dominant-negative mutant of the p85alpha regulatory subunit of PI3K (Deltap85) induced apoptosis. Whereas PTEN and Delta85 both inhibited activation of AKT/protein kinase B, only Deltap85 inhibited c-Jun NH2-terminal kinase (JNK) activity. Cotransfection of the constitutively active mutant Rac-1 (Val12), an upstream activator of JNK, abrogated Deltap85-induced lung cancer cell death, whereas constitutively active mutant mitogen-activated protein kinase kinase (MKK)-1 (R4F) did not. Furthermore, LY294002 induced apoptosis of MKK4-null but not wild-type mouse embryo fibroblasts. Therefore, we propose that, in the setting of wild-type PTEN, PI3K- and MKK4/JNK-dependent pathways cooperate to maintain cell survival.
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PMID:Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent Pathways cooperate to maintain lung cancer cell survival. 1271 85

The effects of Dox (Dox), paclitaxel (Taxol), and serum starvation on the regulation of XIAP (X-linked inhibitor of apoptosis), Bcl-2 phosphorylation, and apoptosis were evaluated in human H460 non-small cell lung cancer cells. Protein kinases that responded to these treatments as prosurvival elements in signal transduction were identified by simultaneously screening phosphorylation of protein kinases in H460 cells cultured in serum-free medium or treated with Dox. We demonstrated that Dox and Taxol induced apoptosis through down-regulation of XIAP and phosphorylation of Bcl-2 in a concentration-dependent manner without changing expression of Bcl-xL in H460 cells. These effects were paralleled by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase protein. We identified that serum starvation and Dox reduced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK), protein kinase C (PKC) alpha/beta and c-Jun NH(2)-terminal kinase. The MEK-specific inhibitor U0126 or PKC inhibitor staurosporine (STP) also down-regulated XIAP expression and induced apoptosis. Thus, our data suggest that apoptosis and down-regulation of XIAP induced by Dox exposure or serum starvation may be mediated through inactivation of the MEK/ERK and PKCalpha/beta pathways. In support of this we demonstrated that the cytotoxic effects of Dox when combined with U0126 or STP were enhanced, i.e., synergistic cytotoxic activities were demonstrated. The synergistic interaction of U0126 or STP with Dox was sequence- and concentration-dependent.
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PMID:Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase enhances chemotherapeutic effects on H460 human non-small cell lung cancer cells through activation of apoptosis. 1288 37

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF-kappaB in vitro and has afforded some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that PS-341 induced growth arrest and apoptosis of NCI-H520 and -H460 non-small cell lung cancer (NSCLC) cells in conjunction with markedly up-regulated levels of p21(waf1) and p53, and down-regulation of bcl-2 protein in these cells. Also, PS-341 caused phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and c-Jun, and enhanced AP-1/DNA binding activities in these cells as measured by western blotting and enzyme-linked immunosorbent assay (ELISA), respectively. Interestingly, when the JNK/c-Jun/AP-1 signal pathway was disrupted by the JNK inhibitor SP600125, the ability of PS-341 to inhibit the growth of NSCLC cells and to up-regulate the levels of p21(waf1) in these cells was blunted, but the expression of p53 was sustained at a high level, suggesting that the JNK/c-Jun/AP-1 signal pathway might mediate the anti-lung cancer effects of PS-341, with p21(waf1) playing the central role. Thus, PS-341 might be useful for the treatment of individuals with NSCLC.
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PMID:Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. 1496 69

Bcl-2 is involved in the progression of human malignancies, but the precise role and mechanism of Bcl-2 for tumor invasion and metastasis remains unclear. In this study, we have investigated the role and mechanism of Bcl-2 on tumor cell invasion and metastasis by using Bcl-2 overexpressing non-small cell lung cancer cells. Matrix metalloproteinases (MMPs) are important proteins involved in the processes of tumor invasion and metastasis. In vitro Matrigel invasion assays showed that Bcl-2 overexpression increased tumor cell invasion by 15-fold. Moreover, Bcl-2 overexpression enhanced in vivo lung metastasis by 4-fold. Consistent with its effect on invasion and metastasis, Bcl-2 overexpression induced not only MMP-2 mRNA and its protein expression, but this also activated the pro-MMP-2 protein to its active form. To explore the induction mechanism of MMP-2 by Bcl-2, we investigated the effects of Bcl-2 overexpression on MMP-2 transcriptional regulation. Nuclear run-on assays showed a 6-fold increase in the transcription rate of MMP-2 mRNA in the Bcl-2 transfectants (H157/Bcl-2) compared with that of the H157/vector control cells (H157/C). Overexpression of Bcl-2 induced the nuclear transcription factor activator protein 1 family, including the c-Jun, JunD, c-Fos, FosB, and Fra-1 proteins. Reporter assays combined with deletion mutagenesis analysis and gel shift assays showed the involvement of activator protein 1 in the activation of MMP-2 promoter activity by Bcl-2. Taken together, we have shown that Bcl-2 promotes tumor invasion and lung metastasis by inducing MMP-2 gene expression through the combined action of transcriptional and posttranslational mechanisms.
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PMID:Bcl-2 promotes invasion and lung metastasis by inducing matrix metalloproteinase-2. 1599 27


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