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)

A surprising finding in the report by Rahman et al. in this issue of Cancer Cell is that forced overexpression of human thymidylate synthase transforms immortalized murine cells into a malignant phenotype. We discuss the possibility that elevated levels of thymidylate synthase noted in some human malignancies may contribute to tumor progression and may also reflect increased levels of its transcriptional activator E2F-1.
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PMID:Thymidylate synthase as an oncogene? 1509 41

The Wnt signalling system controls many fundamental processes during animal development and its deregulation has been causally linked to colorectal cancer. Transduction of Wnt signals entails the association of beta-catenin with nuclear TCF DNA-binding factors and the subsequent activation of target genes. Using genetic assays in Drosophila, we have recently identified a presumptive adaptor protein, Legless (Lgs), that binds to beta-catenin and mediates signalling activity by recruiting the transcriptional activator Pygopus (Pygo). Here, we characterize the beta-catenin/Lgs interaction and show: (1) that it is critically dependent on two acidic amino acid residues in the first Armadillo repeat of beta-catenin; (2) that it is spatially and functionally separable from the binding sites for TCF factors, APC and E-cadherin; (3) that it is required in endogenous as well as constitutively active forms of beta-catenin for Wingless signalling output in Drosophila; and (4) that in its absence animals develop with the same phenotypic consequences as animals lacking Lgs altogether. Based on these findings, and because Lgs and Pygo have human homologues that can substitute for their Drosophila counterparts, we infer that the beta-catenin/Lgs binding site may thus serve as an attractive drug target for therapeutic intervention in beta-catenin-dependent cancer progression.
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PMID:Identification and in vivo role of the Armadillo-Legless interaction. 1529 66

The proteins SKI and SnoN are implicated in processes as diverse as differentiation, transformation and tumor progression. Until recently, SKI was solely viewed as a nuclear protein with a principal function of inhibiting TGF-beta signaling through its association with the Smad proteins. However, new studies suggest that SKI plays additional roles not only inside but also outside the nucleus. In normal melanocytes and primary non-invasive melanomas, SKI localizes predominantly in the nucleus, whereas in primary invasive melanomas SKI displays both nuclear and cytoplasmic localization. Intriguingly, metastatic melanoma tumors display nuclear and cytoplasmic or predominantly cytoplasmic SKI distribution. Cytoplasmic SKI is functional, as it associates with Smad3 and prevents its nuclear localization mediated by TGF-beta. SKI can also function as a transcriptional activator, targeting the beta -catenin pathway and activating MITF and NrCAM, two proteins involved in survival, migration and invasion. Intriguingly, SKI appears to live a dual life, one as a tumor suppressor and another as a transforming protein. Loss of one copy of mouse ski increases susceptibility to tumorigenesis in mice, whereas its overexpression is associated with cancer progression of human melanoma, esophageal, breast and colon. The molecular reasons for such dramatic change in SKI function appear to result from new acquired activities. In this review, we discuss the mechanisms by which SKI regulates crucial pathways involved in the progression of human malignant melanoma.
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PMID:SKI pathways inducing progression of human melanoma. 1598 36

Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF 20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drug-resistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires co-regulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By co-regulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes.
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PMID:Genetic reprogramming of tumor cells by zinc finger transcription factors. 1608 41

Runx2 is an essential transcription factor for skeletal mineralization because it stimulates osteoblast differentiation of mesenchymal stem cells, promotes chondrocyte hypertrophy, and contributes to endothelial cell migration and vascular invasion of developing bones. Runx2 is also expressed during mouse embryo development in nascent mammary gland epithelium. Recent evidence implicates deregulation of Runx2 as a contributing factor in breast cancer-induced osteolysis and invasion, as well as in ectopic vascular calcification. Like other Runt domain proteins, Runx2 is a context-dependent transcriptional activator and repressor of genes that regulate cellular proliferation and differentiation. Proteins that temporally and spatially associate with Runx2 dictate these opposing transcriptional activities. Recent studies have identified several co-repressor proteins that bind to Runx2 to regulate gene expression. These co-factors include histone deacetylases (HDACs), transducin-like enhancer of split (TLE) proteins, mSin3a, and yes-associated protein (YAP). These proteins do not bind DNA themselves and appear to act by preventing Runx2 from binding DNA, altering chromatin structure, and/or by possibly blocking co-activator complexes. The nuclear localization of several of these factors is regulated by extracellular signaling events. Understanding the mechanisms whereby co-repressor proteins affect Runx2 activity during normal cellular development and tumor progression will identify new therapeutic targets for skeletal disorders such as osteoporosis and for bone metastatic cancers.
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PMID:Transcriptional co-repressors of Runx2. 1644 Mar 20

Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor kappaB (NF-kappaB), a TNF-alpha downstream signaling component, is associated with several human illnesses, including cancer, and NF-kappaB controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-kappaB. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-kappaB. The NF-kappaB activation induced by AEG-1 corresponded with degradation of IkappaBalpha and nuclear translocation of p65 that resulted in the induction of NF-kappaB downstream genes. Infection with an adenovirus expressing the mt32IkappaBalpha superrepressor (Ad.IkappaBalpha-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-alpha treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-kappaB. Our findings suggest that activation of NF-kappaB by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype.
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PMID:Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. 1645 7

Invasion of colorectal carcinomas (CC) is characterized by nuclear accumulation of beta-catenin, a key component of the Wnt pathway, in scattered tumor cells. beta-catenin acts in cooperation with T-cell factor (Tcf) HMG-box transcription factors as a transcriptional activator of genes involved in tumor progression. Overexpression of CD97, a molecule that correlates with dedifferentiation and tumor stage in CC, parallels to nuclear translocation of beta-catenin. Here, we investigated whether CD97 is a direct beta-catenin/Tcf target gene. SW480 CC cells were used to mimic the phenotypical switch between central and invasive tumor areas. We demonstrate two-fold higher CD97 expression and nuclear beta-catenin accumulation in cells grown at low density compared to cells cultured at high density, showing membrane-associated beta-catenin. This suggests that CD97 expression correlates with the cellular localization of beta-catenin. However, CD97 mRNA expression levels were not affected by Tcf-1 or Tcf-4 as determined in inducible dominant-negative (dn) Tcf CC cell lines. Furthermore, co-expression of wildtype (wt) or S33A mutated beta-catenin with Tcf-4 did not influence CD97 promoter activity. Inhibition of glycogen synthase kinase (GSK)-3beta, a negative regulator of the canonical Wnt pathway, had no influence on CD97 expression levels. In summary, enhanced CD97 expression in CC cells is regulated independent of beta-catenin/Tcf-4, and is thus not a direct target of the canonical Wnt pathway.
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PMID:CD97 overexpression in tumor cells at the invasion front in colorectal cancer (CC) is independently regulated of the canonical Wnt pathway. 1692 97

A mismatch between metabolic demand and oxygen delivery leads to microenvironmental changes in solid tumors. The resulting tumor hypoxia is associated with malignant progression, therapy resistance and poor prognosis. However, the molecular mechanisms underlying therapy resistance in hypoxic tumors are not fully understood. The hypoxia-inducible factor (HIF) is a master transcriptional activator of oxygen-regulated gene expression. Transformed mouse embryonic fibroblasts (MEFs) derived from HIF-1alpha-deficient mice are a popular model to study HIF function in tumor progression. We previously found increased chemotherapy and irradiation susceptibility in the absence of HIF-1alpha. Here, we show by single-cell electrophoresis, histone 2AX phosphorylation and nuclear foci formation of gammaH2AX and 53BP1, that the number of DNA double-strand breaks (DSB) is increased in untreated and etoposide-treated HIF-deficient MEFs. In etoposide-treated cells, cell cycle control and p53-dependent gene expression were not affected by the absence of HIF-1alpha. Using a candidate gene approach to screen 17 genes involved in DNA repair, messenger RNA (mRNA) and protein of three members of the DNA-dependent protein kinase complex were found to be decreased in HIF-deficient MEFs. Of note, residual HIF-1alpha protein in cancer cells with a partial HIF-1alpha mRNA knockdown was sufficient to confer chemoresistance. In summary, these data establish a novel molecular link between HIF and DNA DSB repair. We suggest that selection of early, non-hypoxic tumor cells expressing low levels of HIF-1alpha might contribute to HIF-dependent tumor therapy resistance.
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PMID:Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1 alpha-deficient mouse embryonic fibroblasts. 1884 80

Caveolin-1 protein has been called a 'conditional tumor suppressor' because it can either suppress or enhance tumor progression depending on cellular context. Caveolin-1 levels are dynamic in non-small-cell lung cancer, with increased levels in metastatic tumor cells. We have shown previously that transactivation of an erythroblastosis virus-transforming sequence (ETS) cis-element enhances caveolin-1 expression in a murine lung epithelial cell line. Based on high sequence homology between the murine and human caveolin-1 promoters, we proposed that ETS proteins might regulate caveolin-1 expression in human lung tumorigenesis. We confirm that caveolin-1 is not detected in well-differentiated primary lung tumors. Polyoma virus enhancer activator 3 (PEA3), a pro-metastatic ETS protein in breast cancer, is expressed at low levels in well-differentiated tumors and high levels in poorly differentiated tumors. Conversely, Net, a known ETS repressor, is expressed at high levels in the nucleus of well-differentiated primary tumor cells. In tumor cells in metastatic lymph node sites, caveolin-1 and PEA3 are highly expressed, whereas Net is now expressed in the cytoplasm. We studied transcriptional regulation of caveolin-1 in two human lung cancer cell lines, Calu-1 (high caveolin-1 expressing) and NCI-H23 (low caveolin-1 expressing). Chromatin immunoprecipitation-binding assays and small interfering RNA experiments show that PEA3 is a transcriptional activator in Calu-1 cells and that Net is a transcriptional repressor in NCI-H23 cells. These results suggest that Net may suppress caveolin-1 transcription in primary lung tumors and that PEA3 may activate caveolin-1 transcription in metastatic lymph nodes.
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PMID:Increased PEA3/E1AF and decreased Net/Elk-3, both ETS proteins, characterize human NSCLC progression and regulate caveolin-1 transcription in Calu-1 and NCI-H23 NSCLC cell lines. 1948 89

Cell migration, which involves acto-myosin dynamics, cell adhesion, membrane trafficking and signal transduction, is a prerequisite for cancer cell metastasis. Here, we report that an actin-dependent molecular motor, unconventional myosin Va, is involved in this process and implicated in cancer metastasis. The mRNA expression of myosin Va is increased in a number of highly metastatic cancer cell lines and metastatic colorectal cancer tissues. Suppressing the expression of myosin Va by lentivirus-based RNA interference in highly metastatic cancer cells impeded their migration and metastasis capabilities both in vitro and in vivo. In addition, the levels of myosin Va in cancer cell lines are positively correlated with the expression of Snail, a transcriptional repressor that triggers epithelial-mesenchymal transition. Repression or overexpression of Snail in cancer cells caused reduced or elevated levels of myosin Va, respectively. Furthermore, Snail can bind to an E-box of the myosin Va promoter and induce its activity, which indicates that Snail might act as a transcriptional activator. These data demonstrate an essential role of myosin Va in cancer cell migration and metastasis, and suggest a novel target for Snail in its regulation of cancer progression.
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PMID:Upregulation of myosin Va by Snail is involved in cancer cell migration and metastasis. 1952 58


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