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)

p73 is a recently cloned tumor suppressor gene that is highly homologous to p53, and the products of both possess similar functions in inhibiting cell growth and inducing apoptosis. Interestingly, the COOH-terminal region of p53 displays no significant homology with that of p73. Moreover, p73 has an additional segment at its COOH terminus. Recently, we have found two mutations of p73 with amino acid substitution (P405R and P425L) in primary neuroblastomas. Because the region (amino acid residues 382-491) contains a glutamine- and proline-rich domain, we hypothesized that it has a transactivation function, and the mutations found in tumors result in loss of function. To test it, we used the yeast GAL4 DNA-binding fusion system. Yeast transformants expressing a GAL4-p73(1-112) or a GAL4-p73alpha(380-513) fusion protein were grown in SD medium lacking histidine and tryptophan and exhibited a significant induction of beta-galactosidase activity. Transient transfection experiments revealed that both of fusion proteins could induce the chloramphenicol acetyltransferase activity in mammalian cells, indicating that the COOH-terminal as well as NH2-terminal regions of p73 had significantly high levels of transactivation activity. Furthermore, the former activity was severely impaired in two naturally occurring mutant forms found in neuroblastomas. These suggest that, unlike p53, p73 has two domains with transactivation function, one in the NH2-terminal region and the other in the COOH-terminal region. Loss of function mutation in the latter might be involved in tumorigenesis and/or tumor progression.
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PMID:Identification of a transactivation activity in the COOH-terminal region of p73 which is impaired in the naturally occurring mutants found in human neuroblastomas. 1038 37

SV40 large T antigen-induced primitive neuroectodermal tumors of the rat provide a model system to study induction and progression of primitive neuroectodermal tumors at the molecular level. A cell line derived from such a tumor reproducibly gave rise to malignant derivatives that ceased large T-antigen expression but harbored a mutant p53 allele with a common mutation at Cys(174) to Tyr (C174Y). To determine whether this p53 mutation contributes to tumor progression, we analyzed mutant C174Y functionally. Co-transfection experiments in Saos-2 cells with mutant or wild-type p53 and reporter genes linked to various p53-responsive promoters revealed that mutant C174Y failed to transcriptionally transactivate the Mdm2, Waf1, Cyclin G and Bax promoters. Loss of transcriptional activation correlated with loss of DNA-binding activity. Moreover, mutant C174Y exhibited a dominant negative effect on co-expressed wild-type p53. The ability of mutant p53 to repress the viral RSV, LTR or SV40 early promoters or the cellular fos promoter was likewise impaired. In contrast, it showed even induction of the fos promoter. Consistent with these observations, mutant C174Y was non-functional in the suppression of Saos-2 cell growth and even conferred a growth advantage to the cells. Surprisingly, mutant C174Y was also impaired in nuclear transport, as revealed by immunofluorescence analyses. Taken together, our results demonstrate that mutant C174Y possesses features that can positively contribute to cancer progression.
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PMID:Tumor-derived p53 mutant C174Y is a gain-of-function mutant which activates the fos promoter and enhances colony formation. 1100 63

Simple retroviruses induce tumors by integrating into the host genome, activating cellular oncogenes and microRNAs, or inactivating tumor suppressor genes. The identification of these genes elucidates molecular mechanisms of tumorigenesis. In this study, we identified avian leukosis virus (ALV) proviral integration sites in rapid-onset B cell lymphomas arising <12 weeks after infection of chicken embryos. By using inverse PCR, 28 unique viral integration sites were identified in rapid-onset tumors. Integrations in the telomerase reverse transcriptase (TERT) promoter/enhancer region were observed in four different tumors, suggesting that this is a common integration site. These provirus integrations ranged from 217 to 2,584 bp upstream of the TERT transcription initiation site and were all in the opposite transcriptional orientation to TERT. Southern blots of tumor samples demonstrated that these integrations are clonal and therefore occurred early in the process of tumorigenesis. Real-time RT-PCR showed overexpression of TERT mRNA in tumors harboring viral integrations in the TERT promoter. Telomerase activity was also up-regulated in these tumors; however, telomere-length alterations were not detected. Furthermore, viral LTR sequences directly enhanced the expression of luciferase reporters containing the TERT promoter sequences. This study documents retroviral up-regulation of cellular TERT by insertional activation to initiate or enhance tumor progression.
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PMID:Telomerase reverse transcriptase expression elevated by avian leukosis virus integration in B cell lymphomas. 1802 87

Immune escape is a critical gateway to malignancy. The emergence of this fundamental trait of cancer represents the defeat of immune surveillance, a potent, multi-armed and essential mode of cancer suppression that may influence the ultimate clinical impact of an early stage tumor. Indeed, immune escape may be a central modifier of clinical outcomes, by affecting tumor dormancy versus progression, licensing invasion and metastasis and impacting therapeutic response. Although relatively little studied until recently, immune suppression and escape in tumors are now hot areas with clinical translation of several new therapeutic agents already under way. The interconnections between signaling pathways that control immune escape and those that control proliferation, senescence, apoptosis, metabolic alterations, angiogenesis, invasion and metastasis remain virtually unexplored, offering rich new areas for investigation. Here, an overview of this area is provided with a focus on the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) and its recently discovered relative IDO2 that are implicated in suppressing T-cell immunity in normal and pathological settings including cancer. Emerging evidence suggests that during cancer progression activation of the IDO pathway might act as a preferred nodal modifier pathway for immune escape, for example analogous to the PI3K pathway for survival or the VEGF pathway for angiogenesis. Small molecule inhibitors of IDO and IDO2 heighten chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion and an initial lead compound entered phase I clinical trials in late 2007. New modalities in this area offer promising ways to broaden the combinatorial attack on advanced cancers, where immune escape mechanisms likely provide pivotal support.
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PMID:Immune escape as a fundamental trait of cancer: focus on IDO. 1831 52

Galectin-1 (Gal-1), a member of a family of evolutionarily conserved glycan-binding proteins, binds specifically to poly-N-acetyllactosamine-enriched glycoconjugates. Through interactions with these glycoconjugates, this protein modulates inflammatory responses and contributes to tumor progression and immune cell homeostasis. The carbohydrate recognition domain includes the single protein tryptophan (Trp68). UV resonance Raman spectroscopy and molecular dynamic simulation were used to examine the change in the environment of the Trp on ligand binding. The UV Raman spectra and the calculated water radial distribution functions show that, while no large structural changes in the protein follow lactose binding, substantial solvent reorganization occurs. These new insights into the microscopic role of water molecules in Gal-1 binding to its specific carbohydrate ligands provides a better understanding of the physicochemical properties of Gal-1-saccharide interactions, which will be useful for the design of synthetic inhibitors for therapeutic purposes.
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PMID:Critical role of the solvent environment in galectin-1 binding to the disaccharide lactose. 1912 29

Immune escape is a characteristic of cancer progression, but its underlying molecular mechanism is still poorly understood. An immunomodulatory protein, indoleamide 2,3-dioxygenase (IDO), is induced by gamma-interferon (IFN-gamma) in several immune cells; those cells are observed in cancer cell microenvironment and can enhance immune escape. Previous studies show that IDO is expressed in the process of tumor formation and associated with cancer cell immune tolerance. By locally degrading tryptophan, IDO inhibits the proliferation of T lymphocytes and induces T cell apoptosis, leading to suppression of T cell response. In this study, (-)-epigallocatechin-3-gallate (EGCG), the major constituent of green tea, is found to significantly inhibit the expression of IDO in human oral cancer cell lines. EGCG suppresses the induction of IDO at transcriptional level. Activation of STAT1 is discovered to play an important role in regulating IDO expression by IFN-gamma. The study results demonstrate that EGCG can inhibit translocation of STAT1 into nucleus in IFN-gamma-stimulated human oral cancer cells. In addition, both tyrosine and serine phosphorylation of STAT1 are revealed to be suppressed by EGCG. Moreover, phosphorylation of PKC-delta, JAK-1, and JAK-2, which are the upstream event for the activation of STAT1, are also inhibited by EGCG in IFN-gamma-stimulated human oral cancer cells. These data show that EGCG inhibited IDO expression by blocking the IFN-gamma-induced JAK-PKC-delta-STAT1 signaling pathway. This study indicates that EGCG is a potential drug for immune and target therapy to enhance cancer therapy by increasing antitumor immunity.
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PMID:Indoleamine 2,3-dioxygenase, an immunomodulatory protein, is suppressed by (-)-epigallocatechin-3-gallate via blocking of gamma-interferon-induced JAK-PKC-delta-STAT1 signaling in human oral cancer cells. 1992 18

Inflammatory signaling plays a key role in tumor progression, and the pleiotropic cytokine interleukin-6 (IL-6) is an important mediator of protumorigenic properties. Activation of the aryl hydrocarbon receptor (AHR) with exogenous ligands coupled with inflammatory signals can lead to synergistic induction of IL6 expression in tumor cells. Whether there are endogenous AHR ligands that can mediate IL6 production remains to be established. The indoleamine-2,3-dioxygenase pathway is a tryptophan oxidation pathway that is involved in controlling immune tolerance, which also aids in tumor escape. We screened the metabolites of this pathway for their ability to activate the AHR; results revealed that kynurenic acid (KA) is an efficient agonist for the human AHR. Structure-activity studies further indicate that the carboxylic acid group is required for significant agonist activity. KA is capable of inducing CYP1A1 messenger RNA levels in HepG2 cells and inducing CYP1A-mediated metabolism in primary human hepatocytes. In a human dioxin response element-driven stable reporter cell line, the EC(25) was observed to be 104nM, while in a mouse stable reporter cell line, the EC(25) was 10muM. AHR ligand competition binding assays revealed that KA is a ligand for the AHR. Treatment of MCF-7 cells with interleukin-1beta and a physiologically relevant concentration of KA (e.g., 100nM) leads to induction of IL6 expression that is largely dependent on AHR expression. Our findings have established that KA is a potent AHR endogenous ligand that can induce IL6 production and xenobiotic metabolism in cells at physiologically relevant concentrations.
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PMID:Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. 2010 48

Bovine leukemia virus expression relies on its chromatin organization after integration into the host cell genome. Proviral latency, which results from transcriptional repression in vivo, represents a viral strategy to escape the host immune system and likely allows for tumor progression. Here, we discriminated two types of latency: an easily reactivable latent state of the YR2 provirus and a 'locked' latent state of the L267 provirus. The defective YR2 provirus was characterized by the presence of nuclease hypersensitive sites at the U3/R junction and in the R/U5 region of the 5'-long terminal repeat (5'-LTR), whereas the L267 provirus displayed a closed chromatin configuration at the U3/R junction. Reactivation of viral expression in YR2 cells by the phorbol 12-myristate 13-acetate (PMA) plus ionomycin combination was accompanied by a rapid but transient chromatin remodeling in the 5'-LTR, leading to an increased PU.1 and USF-1/USF-2 recruitment in vivo sustained by PMA/ionomycin-mediated USF phosphorylation. In contrast, viral expression was not reactivated by PMA/ionomycin in L267 cells, because the 5'-LTR U3/R region remained inaccessible to nucleases and hypermethylated at CpG dinucleotides. Remarkably, we elucidated the BLV 5'-LTR chromatin organization in PBMCs isolated from BLV-infected cows, thereby depicting the virus hiding in vivo in its natural host.
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PMID:Chromatin disruption in the promoter of bovine leukemia virus during transcriptional activation. 2189 Sep 1

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
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PMID:An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. 2245 81

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme with immune-regulating activities in many contexts, such as fetal protection, allograft protection, and cancer progression. Clinical trials are currently evaluating IDO inhibition with 1-methyltryptophan in cancer immunotherapy. However, the exact role of tryptophan catabolism by IDO in human cancers remains poorly understood. Here, we review several studies that correlate IDO expression in human cancer samples and tumor-draining lymph nodes, with relevant clinical or immunologic parameters. IDO expression in various histologic cancer types seems to decrease tumor infiltration of immune cells and to increase the proportion of regulatory T lymphocytes in the infiltrate. The impact of IDO on different immune cell infiltration leads to the conclusion that IDO negatively regulates the recruitment of antitumor immune cells. In addition, increased IDO expression correlates with diverse tumor progression parameters and shorter patient survival. In summary, in the vast majority of the reported studies, IDO expression is correlated with a less favorable prognosis. As we may see results from the first clinical trials with 1-methyltryptophan in years to come, this review brings together IDO studies from human studies and aims to help appreciate outcomes from current and future trials. Consequently, IDO inhibition seems a promising approach for cancer immunotherapy.
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PMID:Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. 2206 54


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