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

The cell surface glycoprotein MUC18, a member of the immunoglobulin superfamily and homologous to several cell adhesion molecules, is associated with tumor progression and the development of metastasis in human malignant melanoma. Immunohistochemical and Northern blot analysis revealed that expression of the antigen is restricted to advanced primary and metastatic melanomas and to cell lines of the neuroectodermal lineage. The genomic sequence encoding the cell surface antigen spans approximately 14 kb and consists of 16 exons. The organization of the gene, which is related to that of the neural cell adhesion molecule N-CAM, shows a structure where each immunoglobulin-related domain is encoded by more than one exon. Sequencing of the putative MUC18 promoter region revealed a G + C-rich promoter lacking conventional TATA and CAAT boxes. Several motifs for binding of transcription factor Sp1 are present in the regulatory region, and only a single transcription start site within a presumed initiator sequence was identified. Sequence elements which might confer melanocyte-specific expression were not detected. Instead, recognition sequences for the transcription factors CREB, AP-2, and c-Myb, as well as CArG-box motifs, were observed. These elements may contribute to the differential regulation of the MUC18 gene in normal and malignant tissues and suggest a role for this putative adhesion molecule in neural crest cells during embryonic development.
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PMID:Genomic organization of the melanoma-associated glycoprotein MUC18: implications for the evolution of the immunoglobulin domains. 837 24

In the human breast cancer cell line MCF-7, the nucleotides ATP gamma S and UTP, acting extracellularly through the purinergic receptor P2Y(2), lead to elevated intracellular calcium levels and increased proliferation. ATP gamma S and UTP treatment of MCF-7 cells activated transcription of the immediate early gene c-fos, an important component in the response to proliferative stimulation. c-fos induction was enhanced by co-treatment with ATP gamma S and a variety of proliferative agents including growth factors, tumour promoters and stress. Stimulation with ATP gamma S or epidermal growth factor (EGF) led to extracellular signal-regulated kinase (ERK) activation and phosphorylation of the transcription factors CREB and Elk-1. Co-stimulation synergistically activated fos expression and notably led to increased levels of ERK, CREB and EGF receptor phosphorylation, as well as hyperphosphorylation of ternary complex factor. Nevertheless, the ERK pathway does not fully account for this synergy, since fos induction was differentially sensitive to the MEK inhibitor U0126, indicating that these two agonists signal differently to this immediate early gene. Thus, extracellular nucleotides co-operate with growth factors to activate genes linked to the proliferative response in MCF-7 cells through activation of specific purinergic receptors, which thereby represent important potential targets for arresting the neoplastic progression of breast cancer cells.
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PMID:Extracellular ATP activates multiple signalling pathways and potentiates growth factor-induced c-fos gene expression in MCF-7 breast cancer cells. 1113 6

The human GSTP1 gene is frequently over-expressed in many human cancers and the expression increases with tumor progression and is associated with a more aggressive biology, poor patient survival, and resistance to therapy. The molecular regulation of the human GSTP1 gene during malignancy is, however, still not well understood. Recently, we reported the presence of a cAMP response element (CRE) in the 5'-region of the human GSTP1 gene, raising the possibility that the cAMP signaling pathway, frequently aberrant in human cancers, may play an important role in the transcriptional activation of the GSTP1 gene in human tumors. In this study, we report that the GSTP1 gene is an early cAMP response gene. Treatment of cells of the human lung carcinoma cell line, Calu-6, with 25 microM forskolin to activate the cAMP pathway resulted in a rapid and significant (sevenfold after 30 min) increase in GSTP1 gene transcripts, which peaked at 12-fold after 4 h. The forskolin-activated GSTP1 transcription in Calu-6 cells was suppressed dose-dependently by a 2-h pre-treatment with 0.1, 1.0, and 10 microM of the adenylate cyclase inhibitor, 2', 5'-dideoxyadenosine. Western blot analysis showed a rapid, fivefold increase, in GSTP1 protein levels after treatment with 25 microM forskolin, with a peak at 2 h post-treatment. The levels of phosphorylated CRE (Ser133) binding protein-1 (CREB-1) increased rapidly, sevenfold at 30 min, and reached 10-fold at 4 h following forskolin treatment. Intracellular cAMP levels also increased rapidly reaching 12-fold at 30 min. Gel mobility shift and supershift assays and DNase/footprinting analyses demonstrated that CREB-1 bZIP and CREB-containing nuclear extracts recognized the GSTP1 CRE with high affinity and specificity. Binding of CREB-1 bZIP to the GSTP1 CRE was abolished when the GSTP1 CRE sequence 5'-CGTCA-3', was mutated at the core nucleotides. Finally, transfection studies using luciferase plasmid constructs showed the GSTP1 CRE to be required for the cAMP-activated gene expression. Together, these findings describe a novel cAMP- and CREB-1-mediated mechanism of transcriptional regulation of the GSTP1 gene and suggest that this may be an important mechanism underlying the increased GSTP1 expression observed in tumors with an aberrant cAMP signaling pathway and in normal cells under conditions of stress, associated with increased intracellular cAMP.
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PMID:Cyclic AMP mediated GSTP1 gene activation in tumor cells involves the interaction of activated CREB-1 with the GSTP1 CRE: a novel mechanism of cellular GSTP1 gene regulation. 1221 Jul 27

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

Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.
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PMID:Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1. 1685 77

Because increased transforming growth factor-beta (TGFbeta) production by tumor cells contributes to cancer progression through paracrine mechanisms, identification of critical points that can be targeted to block TGFbeta production is important. Previous studies have identified the precise signaling components and promoter elements required for TGFbeta induction of TGFbeta1 expression in epithelial cells (Yue, J., and Mulder, K. M. (2000) J. Biol. Chem. 275, 30765-30773). To determine how regulation of TGFbeta3 expression differs from that of TGFbeta1, we identified the precise signaling pathways and transcription factor-binding sites that are required for TGFbeta3 gene expression. By using mutational analysis in electrophoresis mobility shift assays (EMSAs), we demonstrated that the c-AMP-responsive element (CRE) site in the TGFbeta3 promoter was required for TGFbeta-inducible TGFbeta3 expression. Electrophoresis mobility supershift assays indicated that CRE-binding protein 1 (CREB1) and Smad3 were the major components present in this TGFbeta-inducible complex. Furthermore, by using chromatin immunoprecipitation assays, we demonstrated that CREB-1, ATF-2, and c-Jun bound constitutively at the TGFbeta3 promoter (-100 to +1), whereas Smad3 bound at this site only after TGFbeta stimulation. In addition, inhibition of JNK and p38 suppressed TGFbeta induction of TGFbeta3 transactivation, whereas inhibition of ERK and protein kinase A had no effect. Small interfering RNA-CREB1 and small interfering RNA-Smad3 significantly inhibited TGFbeta stimulation of TGFbeta3 promoter reporter activity and TGFbeta3 production. Our results indicate that TGFbeta activation of the TGFbeta3 promoter CRE site, which leads to TGFbeta3 production, is required for TGFbetaRII, JNK, p38, and Smad3 but was independent of protein kinase A, ERK, and Smad4.
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PMID:Requirement of Smad3 and CREB-1 in mediating transforming growth factor-beta (TGF beta) induction of TGF beta 3 secretion. 1689 11

Activating transcription factor 4 (ATF4) belongs to the ATF/CREB (activating transcription factor/cyclic AMP response element binding protein) family of basic region-leucine zipper (bZip) transcription factors, which have the consensus binding site cAMP responsive element (CRE). ATF4 has numerous dimerization partners. ATF4 is induced by stress signals including anoxia/hypoxia, endoplasmic reticulum stress, amino acid deprivation, and oxidative stress. ATF4 expression is regulated transcriptionally, translationally via the PERK pathway of eIF2alpha phosphorylation, and posttranslationally by phosphorylation, which targets ATF4 to proteasomal degradation. ATF4 regulates the expression of genes involved in oxidative stress, amino acid synthesis, differentiation, metastasis and angiogenesis. Transgenic studies have demonstrated ATF4 to be involved in hematopoiesis, lens and skeletal development, fertility, proliferation, differentiation, and long-term memory. ATF4 expression is upregulated in cancer. Since ATF4 is induced by tumour microenvironmental factors, and regulates processes relevant to cancer progression, it might serve as a potential therapeutic target in cancer.
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PMID:Activating transcription factor 4. 1746 66

Oncogenic Ras mutations are early genetic events in colorectal cancer that induce cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) biosynthesis. PGE(2), a downstream product of COX-2, promotes cancer progression by modulating proliferation, apoptosis and angiogenesis. 15-hydroxyprostaglandin dehydrogenase (PGDH) degrades PGE(2) and is down-regulated in colorectal cancer, suggesting that PGDH plays a role in regulating PGE(2) levels and that PGDH over-expression could attenuate Ras-mediated tumorigenesis. Lentiviral transduction was used to express GFP (18.GFP), K-Ras(V12) (18.K-Ras(V12)), PGDH (18.PGDH) or both K-Ras(V12) and PGDH (18.K-Ras(V12).PGDH) in nontumorigenic rat intestinal epithelial (IEC-18) cells. 18.K-Ras(V12) cells exhibited increased phosphorylation of MAP kinases and CREB, proliferation rates, COX-2 and microsomal prostaglandin E synthase (mPGES)-1 expression and PGE(2) and PGI(2) levels. 18.PGDH and 18.K-Ras(V12).PGDH cells had 10(4)-fold increases in PGDH activity with decreased PGE(2) and PGI(2) levels, COX-2 and mPGES-1 expression and proliferation rates. 18.GFP, 18.PGDH, and 18.K-Ras(V12).PGDH cells were unable to grow in soft agar media whereas 18.K-Ras(V12) cells exhibited anchorage-independent cell growth. Xenografts of implanted 18.K-Ras(V12) cells in nu/nu mice produced rapid (2 wk) tumors with uniform antibody staining for COX-2 and mPGES-1 throughout the tumor and elevated PGE(2) levels. Xenografts of 18.K-Ras(V12).PGDH cells exhibited delayed (8 wk) tumor formation with negligible COX-2 and mPGES-1 expression and significantly decreased PGE(2) levels. 18.K-Ras(V12).PGDH tumors had decreased staining of the proliferative marker, Ki-67, and a significant increase in apoptosis in the central region of the tumor. Based on these data, we conclude that PGDH expression suppresses K-Ras(V12)-mediated tumorigenesis in intestinal epithelial cells.
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PMID:15-Hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice. 1805 8

Many tumors down-regulate major histocompatibility complex (MHC) antigen expression to evade host immune surveillance. However, there are very few in vivo models to study MHC antigen expression during tumor spontaneous regression. In addition, the roles of transforming growth factor betal (TGF-beta1), interferon gamma (IFN-gamma), and interleukin (IL)-6 in modulating MHC antigen expression are ill understood. We previously reported that tumor infiltrating lymphocyte (TIL)-derived IL-6 inhibits TGF-beta1 and restores natural killing (NK) activity. Using an in vivo canine-transmissible venereal tumor (CTVT) tumor model, we presently assessed IL-6 and TGF-beta involvement associated with the MHC antigen expression that is commonly suppressed in cancers. IL-6, IFN-gamma, and TGF-beta1, closely interacted with each other and modulated MHC antigen expression. In the presence of tumor-derived TGF-beta1, host IFN-gamma from TIL was not active and, therefore, there was low expression of MHC antigen during tumor progression. TGF-beta1-neutralizing antibody restored IFN-gamma-activated MHC antigen expression on tumor cells. The addition of exogenous IL-6 that has potent anti-TGF-beta1 activity restored IFN-gamma activity and promoted MHC antigen expression. IFN-gamma and IL-6 in combination acted synergistically to enhance the expression of MHC antigen. Thus, the three cytokines, IL-6, TGF-beta1, and IFN-gamma, closely interacted to modulate the MHC antigen expression. Furthermore, transcription factors, including STAT-1, STAT-3, IRF-1, NF-kappaB, and CREB, were significantly elevated after IL-6 and IFN-gamma treatment. We conclude that the host IL-6 derived from TIL works in combination with host IFN-gamma to enhance MHC molecule expression formerly inhibited by TGF-beta1, driving the tumor toward regression. It is suggested that the treatment of cancer cells that constitutively secrete TGF-beta1 should incorporate anti-TGF-beta activity. The findings in this in vivo tumor regression model have potential applications in cancer immunotherapy.
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PMID:Interactions of host IL-6 and IFN-gamma and cancer-derived TGF-beta1 on MHC molecule expression during tumor spontaneous regression. 1825 50

Metastasis-associated protein 1 (MTA1), a master chromatin modifier, has been shown to regulate cancer progression and is widely upregulated in human cancer, including hepatitis B virus-associated hepatocellular carcinomas (HCCs). Here we provide evidence that hepatitis B virus transactivator protein HBx stimulates the expression of MTA1 but not of MTA2 or MTA3. The underlying mechanism of HBx stimulation of MTA1 involves HBx targeting of transcription factor nuclear factor (NF)-kappaB and the recruitment of HBx/p65 complex to the NF-kappaB consensus motif on the relaxed MTA1 gene chromatin. We also discovered that MTA1 depletion in HBx-expressing cells severely impairs the ability of HBx to stimulate NF-kappaB signaling and the expression of target proinflammatory molecules. Furthermore, the presence of HBx in HBx-infected HCCs correlated well with increased MTA1 and NF-kappaB-p65. Collectively, these findings revealed a previously unrecognized integral role of MTA1 in HBx stimulation of NF-kappaB signaling and consequently, the expression of NF-kappaB targets gene products with functions in inflammation and tumorigenesis.
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PMID:NF-kappaB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx. 2001 Aug 75


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