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: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FRA-1, a member of the FOS family of transcription factors, is overexpressed in a variety of human tumors, and contributes to tumor progression. In addition to mitogens, various toxicants and carcinogens persistently induce FRA-1 expression in vitro and in vivo. Although the mitogen induced expression of c-FOS is relatively well understood, it is poorly defined in the case of FRA-1. Our recent analysis of the FRA-1 promoter has shown a critical role for a TRE located at -318 in mediating the TPA-induced expression. The -379 to -283 bp promoter segment containing a critical TRE (-318), however, is insufficient for the induction of FRA-1 promoter. Here, we show that a 40-bp (-276/-237) segment, comprising a TCF binding site and the CArG box (collectively known as serum response element, SRE), and an ATF site, is also necessary for the FRA-1 induction by TPA and EGF. Interestingly, the -283 to +32 bp FRA-1 promoter fragment containing an SRE and an ATF site alone was also insufficient to confer TPA sensitivity to a reporter gene. However, in association with the -318 TRE, the SRE and ATF sites imparted a strong TPA-inducibility to the reporter. Similarly, EGF also required these motifs for the full induction of this gene. Using ChIP assays we show that, in contrast to c-Jun, SRF, Elk1, ATF1 and CREB proteins bind to SRE and ATF sites of the FRA-1 promoter, constitutively. RNAi-mediated knockdown of endogenous SRF, ELK1 and c-JUN protein expression significantly reduced TPA-stimulated FRA-1 promoter activity. Thus, a bipartite enhancer formed by an upstream TRE and the downstream SRE and ATF sites and the cognate factors is necessary and sufficient for the regulation of FRA-1 in response to mitogens.
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PMID:Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements. 1580 62

Nerve growth factor and its high-affinity receptor TrkA are thought to be involved in the progression of various cancers. This study investigated the mechanism that regulates aberrant or increased TrkA expression in various cancer cell lines and in the course of pancreatic cancer progression. We found that the negative cis-acting AP-1-like sequence TGAGCGA was located in the 5'-untranslated region of the TrkA gene. Sodium bisulfite mapping revealed that steady-state TrkA expression correlated positively with the accumulation of methylated CpG around the AP-1-like site. Electrophoretic mobility shift assay showed that the AP-1-like site was bound mainly by c-Jun homodimers; the binding was directly blocked by Sss I methylase-induced methylation or by an excess of oligonucleotides containing consensus AP-1 sequences. Consequently, activation of TrkA gene expression by methylation was considered to be caused by the direct interference of c-Jun binding to the negatively regulating AP-1-like site. Furthermore, the accumulation of methylated CpG around the AP-1-like site was also observed with increased TrkA immunohistochemical staining in cases of advanced pancreatic adenocarcinoma with extensive perineural invasion. Unlike global methylation at CpG islands that leads to gene silencing, specific methylation at non-CpG islands would play a crucial epigenetic role in the versatility and plasticity of TrkA expression during cancer progression.
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PMID:Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression. 1587 Jun 92

The scaffold protein Islet-Brain1/c-Jun amino-terminal kinase Interacting Protein-1 (IB1/JIP-1) is a modulator of the c-Jun N-terminal kinase (JNK) activity, which has been implicated in pleiotrophic cellular functions including cell differentiation, division, and death. In this study, we described the presence of IB1/JIP-1 in epithelium of the rat prostate as well as in the human prostatic LNCaP cells. We investigated the functional role of IB1/JIP-1 in LNCaP cells exposed to the proapoptotic agent N-(4-hydroxyphenyl)retinamide (4-HPR) which induced a reduction of IB1/JIP-1 content and a concomittant increase in JNK activity. Conversely, IB1/JIP-1 overexpression using a viral gene transfer prevented the JNK activation and the 4-HPR-induced apoptosis was blunted. In prostatic adenocarcinoma cells, the neuroendocrine (NE) phenotype acquisition is associated with tumor progression and androgen independence. During NE transdifferentiation of LNCaP cells, IB1/JIP-1 levels were increased. This regulated expression of IB1/JIP-1 is secondary to a loss of the neuronal transcriptional repressor neuron restrictive silencing factor (NRSF/REST) function which is known to repress IB1/JIP-1. Together, these results indicated that IB1/JIP-1 participates to the neuronal phenotype of the human LNCaP cells and is a regulator of JNK signaling pathway.
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PMID:IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. 1589 66

We immunohistochemically examined 75 human colorectal neoplasms (adenoma, 27; adenocarcinoma, 24; neuroendocrine carcinoma, 24) for the expression of activator protein (AP)-1 family proteins. Nuclear and cytoplasmic expression levels of c-Jun and Fra-1 proteins were markedly elevated in adenomas, adenocarcinomas and neuroendocrine carcinomas compared with nonneoplastic colorectal epithelial cells. JunB also was overexpressed in these tumors but with a predominantly cytoplasmic staining pattern. Overexpression of Fra-2 was evident in carcinomas but less frequent in adenomas. Expression levels of JunD and c-Fos were high in nonneoplastic colorectal epithelial cells and remained so in neoplasms. FosB was undetectable in nonneoplastic and neoplastic colorectal tissues. Neuroendocrine carcinomas exhibited an AP-1 expression profile similar to adenocarcinomas except for infrequent overexpression of c-Jun in poorly differentiated variants. Hierarchical clustering separated the majority of malignant from benign tumors based on AP-1 expression patterns. AP-1 transcription factor family members are expressed differentially in nonneoplastic and neoplastic colorectal tissues. Up-regulation of c-Jun and Fra-1 is an early event in human colorectal tumorigenesis. Overexpression of Fra-2 may participate in tumor progression.
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PMID:Differential expression of the AP-1 transcription factor family members in human colorectal epithelial and neuroendocrine neoplasms. 1592 59

S100A7 is among the most highly expressed genes in preinvasive breast cancer, is a marker of poor survival when expressed in invasive disease, and promotes breast tumor progression in experimental models. To explore the mechanism of action, we examined the role of S100A7 in cell survival and found that overexpression of S100A7 in MDA-MB-231 cell lines promotes survival under conditions of anchorage-independent growth. This effect is paralleled by increased activity of nuclear factor-kappaB (3-fold) and phospho-Akt (4-fold), which are known to mediate prosurvival pathways. S100A7 and phospho-Akt are also correlated in breast tumors examined by immunohistochemistry (n = 142; P < 0.0001; r = 0.34). To explore the underlying mechanism, we examined the role of a putative c-Jun activation domain-binding protein 1 (Jab1)-binding domain within S100A7 using a panel of MDA-MB-231 breast cell lines stably transfected with either S100A7 or S100A7 mutated at the Jab1 domain. Structural analysis by three-dimensional protein modeling, immunoprecipitation, and yeast two-hybrid assay and functional analysis using transfected reporter gene and Western blot assays revealed that the in vitro effects of S100A7 on phospho-Akt and the nuclear factor-kappaB pathway are dependent on the Jab1-binding site and the interaction with Jab1. Enhanced epidermal growth factor receptor signaling was also found to correlate with the increased phospho-Akt. Furthermore, the Jab1-binding domain is also necessary for the enhanced tumorigenicity conferred by S100A7 expression in murine xenograft tumors in vivo. We conclude that the S100A7-Jab1 pathway acts to enhance survival under conditions of cellular stress, such as anoikis, which may promote progression of breast cancer.
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PMID:The S100A7-c-Jun activation domain binding protein 1 pathway enhances prosurvival pathways in breast cancer. 1599 44

Metastasis is a significant event in cancer progression and continues to pose the greatest challenge for a cancer cure. Defining genes that control metastasis in vivo may provide new targets for intervening in this process with profound therapeutic implications. Melanoma differentiation associated gene-9 (mda-9) was initially identified by subtraction hybridization as a novel gene displaying biphasic expression during terminal differentiation in human melanoma cells. Mda-9, also known as syntenin, is a PDZ-domain protein overexpressed in many types of human cancers, where it is believed to function in tumor progression. However, a functional role of mda-9/syntenin in tumor growth and metastasis and the signaling pathways involved in mediating these biological activities remain to be defined. Evidence is now provided, using weakly and highly metastatic isogenic melanoma variants, that mda-9/syntenin regulates metastasis. Expression of mda-9/syntenin correlates with advanced stages of melanoma progression. Regulating mda-9/syntenin expression using a replication-incompetent adenovirus expressing either sense or antisense mda-9/syntenin modifies the transformed phenotype and alters metastatic ability in immortal human melanocytes and metastatic melanoma cells in vitro and in vivo in newborn rats. A direct relationship is observed between mda-9/syntenin expression and increased phosphorylation of focal adhesion kinase, c-Jun-NH2-kinase, and p38. This study provides the first direct link between mda-9/syntenin expression and tumor cell dissemination in vivo and indicates that mda-9/syntenin expression activates specific signal transduction pathways, which may regulate melanoma tumor progression. Based on its ability to directly alter metastasis, mda-9/syntenin provides a promising new focus for melanoma cancer research with potential therapeutic applications for metastatic diseases.
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PMID:mda-9/Syntenin: a positive regulator of melanoma metastasis. 3157 35

4-Hydroxynonenal (HNE) has been demonstrated to exert its antiproliferative effect by up-regulating the c-Jun-N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family (MAPKs). Transforming growth factor-beta1 (TGF-beta1) is the major negative regulatory factor in controlling cell proliferation, and Smads are its intracellular transducers. Recent data on human colon adenocarcinoma has shown a low HNE content paralleled by a marked alteration of TGF-beta1 levels within the tumor mass. The two events appear related because of the demonstrated marked ability of HNE to up-regulate expression and synthesis of TGF-beta1; the combined decreases of HNE and TGF-beta1 found in cancer cells provide a favorable condition for neoplastic progression. Furthermore, HNE is likely able to interact with the cytokine to enhance apoptosis and increase intracellular reactive oxygen species (ROS) formation in the CaCo-2 colon carcinoma cell line. The probable mechanism whereby HNE and TGF-beta1 interact to induce apoptosis is through cross-talk between the main signaling pathways of the two molecules (JNK and Smads), and the observed ROS production might only contribute to amplifying the apoptotic pathways. The network between the two signaling pathways here involved is now under investigation.
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PMID:4-hydroxynonenal and TGF-beta1 concur in inducing antiproliferative effects on the CaCo-2 human colon adenocarcinoma cell line. 1640 84

Programmed cell death 4 (Pdcd4) suppresses neoplastic transformation by inhibiting the activation of c-Jun and consequently AP-1-dependent transcription. We report that Pdcd4 blocks c-Jun activation by inhibiting the expression of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1)/hematopoietic progenitor kinase 1, a kinase upstream of Jun N-terminal kinase (JNK). cDNA microarray analysis of Pdcd4-overexpressing RKO human colon carcinoma cells revealed MAP4K1 as the sole target of Pdcd4 on the JNK activation pathway. Cotransfection of a MAP4K1 promoter-reporter with Pdcd4 demonstrated inhibition of transcription from the MAP4K1 promoter. Ectopic expression of Pdcd4 in metastatic RKO cells suppressed invasion. MAP4K1 activity is functionally significant in invasion, as overexpression of a dominant negative MAP4K1 (dnMAP4K1) mutant in RKO cells inhibited not only c-Jun activation but also invasion. Overexpression of a MAP4K1 cDNA in Pdcd4-transfected cells rescued the kinase activity of JNK. Thus, Pdcd4 suppresses tumor progression in human colon carcinoma cells by the novel mechanism of down-regulating MAP4K1 transcription, with consequent inhibition of c-Jun activation and AP-1-dependent transcription.
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PMID:Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. 1644 43

Avian fibroblasts transformed simultaneously by the v-myc and v-mil(raf) oncogenes of acute leukemia and carcinoma virus MH2 contain elevated levels of c-Fos and c-Jun, major components of the transcription factor complex AP-1. To define specific transcriptional targets in these cells, subtractive hybridization techniques were employed leading to the identification of strongly upregulated genes including OPN (osteopontin), 126MRP, and rac2. OPN is a cytokine and cell attachment protein which has been implicated in human tumor progression and metastasis, the calcium binding 126MRP protein is related to the human S100 protein family involved in invasive cell growth, and the Rac2 protein belongs to the Rho family of small GTPases regulating actin reorganization and cell migration. Promoter analysis indicated that OPN activation is mediated by a non-consensus AP-1 binding site located close to the transcription start site. Electrophoretic mobility shift assays, chromatin immunoprecipitation and transcriptional reporter gene analyses showed that c-Fos and c-Jun bind specifically to this site and that c-Fos efficiently transactivates the OPN promoter. High-level expression of OPN, 126MRP, or Rac2 proteins from a retroviral vector led to partial cell transformation, documented by morphological changes and anchorage-independent growth. The specific activation in v-myc/v-mil(raf)-transformed cells of target genes with intrinsic oncogenic potential may provide an explanation for the longstanding observation that concomitant expression of these oncogenes leads to strongly enhanced oncogenicity in vivo and in vitro compared to cell transformation by v-myc or v-mil(raf) alone.
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PMID:Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis. 1649 Nov 16

Mammary tumor cells are required to degrade the surrounding matrix and disseminate in order to metastasize, and both of these processes are controlled by a tumor cell-signaling network that remains poorly defined. MEKK1 is a MAPKKK that regulates both the extracellular signal regulated kinase (ERK1/2) and the c-Jun amino terminal kinase (JNK) signaling pathways. MEKK1 signaling regulates migration through control of cell adhesion and is required for inducible expression of urokinase-type plasminogen activator (uPA). MEKK1-deficient mice with mammary gland-targeted expression of the polyoma middle T antigen (PyMT) transgene develop primary mammary tumors at a rate and frequency similar to wild-type littermates, indicating that MEKK1 deficiency does not affect PyMT-mediated transformation. However, MEKK1-/- mice display significantly delayed tumor cell dissemination and lung metastasis. Delayed MEKK1-dependent tumor dissemination is associated with markedly reduced tumor uPA expression, gelatinase activity, and prolonged tumor basement membrane integrity. siRNA-mediated MEKK1 knockdown inhibits uPA activity, cell migration and invasion in MDA-MB-231 human breast cancer cells. Thus MEKK1 controls tumor progression by regulating both the migration and proteolysis aspects of tumor cell invasiveness. To our knowledge, this is the first example of a MAPKKK that regulates metastasis through control of tumor invasiveness.
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PMID:MEKK1 controls matrix degradation and tumor cell dissemination during metastasis of polyoma middle-T driven mammary cancer. 1656 86


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