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 early genes E6 and E7 from human papillomaviruses (HPVs) play a key role in the development of cervical cancer. Modulation of E6 and E7 gene expression may alter tumour progression; therefore, modifiers of viral transcription such as hormones or growth factors are potential risk factors in cancer development. We have analysed the effects of epidermal growth factor (EGF) on E6/E7 mRNA from human papillomavirus type 16 (HPV-16) by Northern blot in two cell lines, SiHa cervical carcinoma cells, and HPK IA, an HPV-16-immortalized keratinocyte cell line. E6/E7 mRNA is EGF-inducible in SiHa cells, with the earliest response after 2 h. In contrast, in HPK IA cells no increase in E6/E7 RNA is observed, suggesting a differential EGF response of viral transcription in tumour cells compared with keratinocytes. We demonstrate that the cell type-specific HPV-16 enhancer is a target of EGF-induced signals, as its activity is amplified by EGF in SiHa cell transfections. However, when transfected into HPK IA keratinocytes, the viral enhancer shows no EGF response. The enhancer contains two binding sites for the transcription factor AP-1, a potential mediator of the EGF signalling cascade. Enhancer subfragments with single AP-1 binding sites are also EGF-responsive in SiHa cells. Mutating either AP-1 site in the complete enhancer decreases the EGF response, whereas a double mutation causes a complete loss of EGF regulation, suggesting that the EGF induction of HPV-16 early transcription requires AP-1 activation. We conclude that alterations of EGF responsiveness that increase viral oncogene expression may contribute to cervical cancer progression.
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PMID:Epidermal growth factor induction of human papillomavirus type 16 E6/E7 MRNA in tumor cells involves two AP-1 binding sites in the viral enhancer. 763 75

Considering the involvement of a redox-regulatory pathway in the expression of human papillomaviruses (HPVs), HPV type 16 (HPV-16)-immortalized human keratinocytes were treated with the antioxidant pyrrolidine-dithiocarbamate (PDTC). PDTC induces elevated binding of the transcription factor AP-1 to its cognate recognition site within the viral regulatory region. Despite of increased AP-1 binding, normally indispensable for efficient HPV-16 transcription, viral gene expression was selectively suppressed at the level of initiation of transcription. Electrophoretic mobility supershift assays showed that the composition of the AP-1 complex, predominantly consisting of Jun homodimers in untreated cells, was altered. Irrespective of enhanced c-fos expression, c-jun was phosphorylated and became primarily heterodimerized with fra-1, which was also induced after PDTC incubation. Additionally, there was also an increased complex formation between c-jun and junB. Because both fra-1 and junB overexpression negatively interferes with c-jun/c-fos trans-activation of AP-1-responsive genes, our results suggest that the observed block in viral transcription is mainly the consequence of an antioxidant-induced reconstitution of the AP-1 transcription complex. Since expression of the c-jun/c-fos gene family is tightly regulated during cellular differentiation, defined reorganization of a central viral transcription factor may represent a novel mechanism controlling the transcription of pathogenic HPVs during keratinocyte differentiation and in the progression to cervical cancer.
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PMID:Antioxidant-induced changes of the AP-1 transcription complex are paralleled by a selective suppression of human papillomavirus transcription. 898 58

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) is an important target for preventing epithelial malignancies. Little is known, however, about the expression of COX-2 in gynecological malignancies. By immunoblot analysis, COX-2 was detected in 12 of 13 cases of cervical cancer but was undetectable in normal cervical tissue. Immunohistochemistry revealed COX-2 in malignant epithelial cells. COX-2 was also expressed in cervical intraepithelial neoplasia. The mechanism by which COX-2 is up-regulated in cervical cancer is unknown. Because the epidermal growth factor (EGF) receptor is commonly overexpressed in cervical cancer, we investigated whether EGF could induce COX-2 in cultured human cervical carcinoma cells. Treatment with EGF markedly induced COX-2 protein, COX-2 mRNA, and stimulated COX-2 promoter activity. The induction of COX-2 by EGF was suppressed by inhibitors of tyrosine kinase activity, phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p38 mitogen-activated protein kinase. Moreover, overexpressing dominant-negative forms of extracellular signal-regulated kinase 1, c-Jun NH2-terminal kinase, p38, and c-Jun blocked EGF-mediated induction of COX-2 promoter activity. Taken together, these findings suggest that deregulation of the EGF receptor signaling pathway may lead to enhanced COX-2 expression in cervical cancer.
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PMID:Cyclooxygenase-2 is overexpressed in human cervical cancer. 1123

Human Papilloma Virus (HPV) is associated in most instances with cervical cancer. The HPV oncoproteins target P53 protein for degradation, leading to deregulation of cell cycle. We investigated whether stabilization of P53 in cervical cancer cells, by downregulating HPV transcription would restore the apoptotic ability of these cells. Our findings show that vitamin C downregulates the redox sensitive transcription factor AP-1 and decreases one of its transcription targets HPV E6, and stabilizes P53. This was associated with an increase in Bax and decrease in Bcl-2 and telomerase activity. Accumulation of P53 and its target gene bax then sensitized HeLa cells to cell-cycle arrest, cell death/apoptosis induced by cisplatin, and etoposide. Increasing drug sensitivity of cervical carcinoma cells by stabilizing P53 using vitamin C is a novel approach and has potential clinical relevance.
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PMID:Vitamin C augments chemotherapeutic response of cervical carcinoma HeLa cells by stabilizing P53. 1140 73

We investigated the signalling pathways by which epidermal growth factor (EGF) modulates paclitaxel-induced apoptosis in SiHa human cervical cancer cells. SiHa cells exposed to paclitaxel underwent apoptosis, which was strongly inhibited by EGF. This inhibition of apoptosis by EGF was not altered by pharmacological blockade of phosphatidylinositol 3'-OH kinase (PI-3K) with the PI-3K specific inhibitor LY294002 or blockade of the mitogen-activated protein kinase (MAPK) kinase (MEK) with the MEK specific inhibitor PD98059, or by transfection of the cells with PI-3K or MEK dominant-negative expression vectors. EGF did not stimulate PI-3K/Akt, MEK/MAPK, or p38 MAPK activity in SiHa cells but did transiently activate the c-Jun NH2-terminal kinase (JNK). Co-exposure of SiHa cells to SB202190 at concentrations that inhibit JNK abolished the protective effect of EGF on SiHa cells against paclitaxel-induced apoptosis. Our findings indicate that the JNK signaling pathway plays an important role in EGF-mediated protection from paclitaxel-induced apoptosis in SiHa cells.
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PMID:Involvement of JNK-mediated pathway in EGF-mediated protection against paclitaxel-induced apoptosis in SiHa human cervical cancer cells. 1146 Oct 94

Activator protein-1 (AP1) is a dimeric protein, consisting either of homodimers between c-Jun, JunB, and JunD of by heterodimers with members of the Fos-family by physically interacting via a "leucine zipper" region. AP1 is an important transcription factor initially identified as a DNA binding protein that bound to enhancer sequences of the human metallothionein IIA gene. The protein components of AP1 are encoded by a set of genes known as "immediate-early" genes that can be activated by a variety of growth factors and mitogens through several different signaling pathways. Until recently, AP1 was considered a transcription factor expressed in most tissues to regulate cellular and viral genes now, it is becoming evident that AP1 can be involved in tissue-specific regulation of target genes due to the differential combination of the components of this important transcription factor. AP1 plays a crucial role during human papillomavirus (HPV) early gene expression, in particular of the expression of E6 and E7 oncoproteins. The HPV are a group of DNA viruses consisting of more than 80 different genotypes. Some of these HPV, know as high risk HPV, are important etiologic agents of uterine-cervical cancer (CaCu). Of the different types of cancer, CaCu is one of the most frequent among women worldwide, constituting the second death cause due to neoplasia. During cellular transformation, HPV infect basal cells in stratified epithelium; their DNA integrate into the host genome usually through the E2 gene; as these cells differentiate and migrate into the upper layer of the epithelium, viral oncogene are expressed blocking their differentiation. Mutagenesis in AP1 sites belonging to the HPV promoter region (LCR) completely abolished the HPV promoter activity in different cell lines; these results and biochemistry assays on this AP1 transcription factor, that includes protein-protein interactions between AP1 and another factors as E7 from HPV, and YY-1; the post-translattional modification and, the retinoic acid interaction; suggest a role for this AP1 factor in tissue-specific transcription of the human papillomavirus.
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PMID:[Possible role of transcription factor AP1 in the tissue-specific regulation of human papillomavirus]. 1218 93

Multiple epidemiologic studies show that adeno-associated virus (AAV) is negatively associated with cervical cancer (CX CA), a cancer which is positively associated with human papillomavirus (HPV) infection. Mechanisms for this correlation may be by Rep78's (AAV's major regulatory protein) ability to bind the HPV-16 p97 promoter DNA and inhibit transcription, to bind and interfere with the functions of the E7 oncoprotein of HPV-16, and to bind a variety of HPV-important cellular transcription factors such as Sp1 and TBP. c-Jun is another important cellular factor intimately linked to the HPV life cycle, as well as keratinocyte differentiation and skin development. Skin is the natural host tissue for both HPV and AAV. In this article it is demonstrated that Rep78 directly interacts with c-Jun, both in vitro and in vivo, as analyzed by Western blot, yeast two-hybrid cDNA, and electrophoretic mobility shift-supershift assay (EMSA supershift). Addition of anti-Rep78 antibodies inhibited the EMSA supershift. Investigating the biological implications of this interaction, Rep78 inhibited the c-Jun-dependent c-jun promoter in transient and stable chloramphenicol acetyl-transferase (CAT) assays. Rep78 also inhibited c-Jun-augmented c-jun promoter as well as the HPV-16 p97 promoter activity (also c-Jun regulated) in in vitro transcription assays in T47D nuclear extracts. Finally, the Rep78-c-Jun interaction mapped to the amino-half of Rep78. The ability of Rep78 to interact with c-Jun and down-regulate AP-1-dependent transcription suggests one more mechanism by which AAV may modulate the HPV life cycle and the carcinogenesis process.
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PMID:The adeno-associated virus major regulatory protein Rep78-c-Jun-DNA motif complex modulates AP-1 activity. 1451 94

The molecular mechanism of hypoxia-induced apoptosis has not been clearly elucidated. In this study, we investigated the involvement of extracellular signal-regulated protein kinase (ERK 1/2) in hypoxia-induced apoptosis using cobalt chloride in HeLa human cervical cancer cells. The cobalt chloride was used for the induction of hypoxia, and its IC(50) was 471.4 microM. We demonstrated the DNA fragmentation after incubation with concentrations more than 50 microM cobalt chloride for 24 h, and also evidenced the morphological changes of the cells undergoing apoptosis with electron microscopy. Next, we examined the signaling pathway of cobalt chloride-induced apoptosis in HeLa cells. ERK1/2 activation occurred 6 and 9 h after treatment with 600 microM cobalt chloride. Meanwhile, the pretreatment of the MEK 1 inhibitor (PD98059) completely blocked the cobalt chloride-induced ERK 1/2 activation. At the same time, the activated ERK 1/2 translocated into the nucleus and phosphorylated its transcriptional factor, c-Jun. In addition, the pretreatment of PD98059 inhibited the cobalt chloride-induced DNA fragmentation and apoptotic cell death. These results suggest that cobalt chloride is able to induce apoptotic activity in HeLa cells, and its apoptotic mechanism may be associated with signal transduction via ERK 1/2.
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PMID:Cobalt chloride-induced apoptosis and extracellular signal-regulated protein kinase activation in human cervical cancer HeLa cells. 1453 30

The transcription factor AP-1 plays a central role in the transcriptional regulation of specific types of high-risk human papillomaviruses (HPVs) such as HPV16 and HPV18, which are etiologically associated with the development of cancer of the uterine cervix in women. In our study, we investigated the AP-1 binding activity and the expression pattern of different members of the AP-1 transcription factor family (c-Jun, JunB, JunD, c-Fos, FosB, Fra-1 and Fra-2) in different grades of cervical lesions starting from mild dysplasia to invasive cervical tumors, including normal control tissues, using specific antibodies raised against each of the AP-1 members. Results indicate that though AP-1 showed high binding activity and the majority of its members were highly expressed in tumor tissues, there is a distinct pattern of gradual increase of c-fos and a concomitant decrease of fra-1 expression that perfectly match the progression of cervical lesions. While c-fos is highly expressed in invasive cervical tumor, the expression of fra-1 becomes almost nil or absent, but the reverse is true in both controls and early precancerous lesions. These findings corroborate the results obtained in the cervical cancer cell line, HeLa. Interestingly, despite very low or absent AP-1 binding in normal as well as in premalignant lesions, AP-1 transcription and its binding activity was found to be very high in malignant tissues showing a preferential heterodimerization of c-fos with JunB instead of its canonical dimerization partner c-jun. Both in vivo and in vitro studies demonstrate that the overexpression of c-fos and downregulation of fra-1 expression as well as a change in the dimerization pattern of the AP-1 complex seem to play a crucial role during progression to malignancy. In a previous study, we demonstrated that a synthetic antioxidant, pyrrolidine dithiocarbamate (PDTC) can selectively downregulate HPV expression in human keratinocytes and cervical cancer cell lines. Since a redox regulatory pathway is involved in the expression of HPV that can be modulated by an antioxidant-induced reconstitution of the AP-1 transcription complex, we have used curcumin (diferuloylmethane), an active component of the perennial herb turmeric, which is a potent antioxidant and is well-known for its antiinflammatory and anticarcinogenic activity, to modulate the transcription of AP-1 and HPV. We demonstrate for the first time that curcumin can selectively downregulate HPV18 transcription as well as the AP-1 binding activity in HeLa cells. Most interestingly, curcumin can reverse the expression dynamics of c-fos and fra-1 in this tumorigenic cell line, mimicking the expression pattern observed in normal controls or precancerous lesions. Observation of curcumin-mediated complete downregulation of AP-1 binding activity and reversal of c-fos/fra-1 transcription to a normal state in tumorigenic HeLa cells represents a novel mechanism that can control transcription of pathogenic HPVs during keratinocyte differentiation and progression of cervical cancer. Our study thus provides a basis for developing a novel therapeutic approach to control pathogenic HPV infection by using potent antioxidative agents, such as curcumin.
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PMID:Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. 1551 44

Cervical cancer is a leading cause of death in developing countries and is the second highest occurring cancer in women all over the world. The progression of cancer is a multistep process affecting aspects of cellular function such as proliferation, differentiation and apoptosis. Mitogen activated protein kinases (MAPKs), which include p38-MAPK, c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated kinases (ERKs) are closely associated with cell proliferation and apoptosis and the balance between them could determine a cell's fate. Despite the expanding research effort in vitro, little is known about MAPK activation in clinical specimens of cervical cancer. Therefore, the aim of this ex vivo study was to correlate the phosphorylation status (activity) of MAPKs (p38-MAPK, JNK and ERK), as well as poly (ADP-ribose) polymerase (PARP) and caspase-3 (two cellular markers of apoptosis), during the different stages of cervical carcinogenesis, to observe whether correlations between MAPK activities and apoptosis during the disease process exist. Decreased p38-MAPK phosphorylation was found in the carcinoma (Ca) group) compared to the normal tissues, as well when the low grade squamous intraepithelial lesion--LSIL) group and high grade squamous intraepithelial lesion--HSIL) group were compared with the Ca group. Interestingly, a significant decrease in ERK44 phosphorylation was observed in Ca when compared to LSIL and HSIL. There was also a significant decrease in JNK phosphorylation in Ca when compared with normal tissue and HSIL. As expected, caspase-3 activation and PARP cleavage was significantly lower in Ca when compared with normal tissue. Our results present the first evidence of in vivo involvement of MAPKs in cervical cancer and indicate a possible correlation between MAPK activities and apoptosis in the disease process.
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PMID:Ex vivo study of MAPK profiles correlated with parameters of apoptosis during cervical carcinogenesis. 1592 65


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