UMLS:C0178874 - FACTA Search

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

Queuosine-deficient tRNAs are often observed in neoplastic cells. In order to determine possible sites for malfunction of the multistep queuosine modification system, comprehensive studies were performed on two human neoplastic cell lines, the HxGC(3) colon adenocarcinoma and the MCF-7 breast adenocarcinoma, which are 100 and 50-60% queuosine deficient, respectively. These results were compared with data obtained from normal human fibroblast (HFF) cultures which maintain 100% queuosine-modified tRNA populations. Queuine uptake in all three cell types was similar and each demonstrated activation by protein kinase C (PKC). However, incorporation of queuine into tRNA by tRNA:guanine ribosyltransferase (TGRase; E.C. 2.4.2.24) and PKC-catalyzed activation of this enzyme occurred only in HFF and MCF-7 cells. The HxGC(3) cell line exhibited no TGRase activity as was expected. Treatment with 5-azacytidine (5-azaC) induced TGRase activity to a level 20% of that in HFF and MCF-7 cells; however, this 5-azaC-induced TGRase activity was not regulated by PKC. Salvage of the queuine base from tRNA degradation products has been shown in mammalian cells and was measured in the HFF cells. However, salvage activity in the MCF-7 cell line was deficient. Therefore, it was shown by direct measurements that the HxGC(3) cell line is completely lacking in queuosine-modified tRNA due to loss of functional TGRase, while the MCF-7 cell line has an inefficient queuine salvage mechanism resulting in a significant deficiency of queuosine-modified tRNA. These techniques can be applied to any cultured cell types to determine specific lesions of the queuosine modification system, which have been suggested to be associated with neoplastic progression.
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PMID:Determination of queuosine modification system deficiencies in cultured human cells. 1047 83

Rac1 is a member of the Ras superfamily of small GTPases involved in signal transduction pathways that induce the formation of lamellipodia, stimulate cell proliferation and activate the JNK/SAPK protein kinase cascade. Here we describe that amplification by RT-PCR of the entire Rac1 coding sequence from a series of human adult and fetal tissues revealed beside the expected Rac1 cDNA, a variant product which contained additional 57 nucleotides between codons 75 and 76. This variant resulted in an in-frame insertion of 19 new amino acids immediately behind the switch II region, including two potential threonine phosphorylation sites for casein kinase II and protein kinase C. Primers designed within and downstream of the inserted nucleotide sequence allowed isolation of a genomic clone with intronic consensus sequences demonstrating that the insertion corresponds to a novel, yet undescribed exon 3b. This Rac1 splice variant, designated Rac1b, was predominantly identified in skin and epithelial tissues from the intestinal tract. Most notably, the expression of rac1b versus rac1 was found to be elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues. We suggest that the 19 amino acid-insertion following the switch II region may create a novel effector binding site in rac1b, and thus participate in signaling pathways related to the normal or neoplastic growth of the intestinal mucosa.
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PMID:Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. 1059 94

The HMGI(Y) family of "high mobility group" nonhistone proteins are architectural transcription factors whose overexpression is highly correlated with both cancerous transformation and increased malignancy and metastatic potential of tumors in vivo. Here we report on the types of posttranslational modifications found in vivo on the HMG-I and HMG-Y proteins isolated from two human breast epithelial cell lines, MCF-7 and MCF-7/PKC-alpha, that represent different stages of neoplastic progression. The MCF-7 cell line exhibits many characteristics of normal breast epithelial cells and does not form tumors when injected into nude mice, whereas the MCF-7/PKC-alpha cell line, a derivative of MCF-7 that expresses a transgene coding for the enzyme protein kinase C-alpha (PKC-alpha), is both malignant and highly metastatic. Using MALDI mass spectrometry, we show that the HMG-Y protein is more highly modified than the HMG-I protein in both the MCF-7 and the MCF-7/PKC-alpha cells. Significantly, the HMG-Y protein isolated from the highly metastatic MCF-7/PKC-alpha cells possesses a unique constellation of phosphorylations, methylations, and acetylations not found on the HMG-I protein isolated from either the MCF-7 or MCF-7/PKC-alpha cells. We further demonstrate that some of the same amino acid residues phosphorylated on recombinant HMGI(Y) proteins by purified PKC in vitro are also phosphorylated on the HMG-I(Y) proteins isolated from MCF-7/PKC-alpha cells, suggesting that PKC phosphorylates these proteins in vivo. Quantitative substrate binding analyses indicate that the biochemical modifications present on the HMG-I and HMG-Y proteins differentially influence the ability of these proteins to interact with both A.T-rich DNA substrates and nucleosome core particles in vitro, suggesting a similar modulation of such binding affinities in vivo. To our knowledge, this is the first demonstration of differences in the types of in vivo biochemical modifications found on the HMG-I and HMG-Y proteins in cells and also the first experimental evidence suggesting a possible linkage between such posttranslational modifications and the neoplastic potential of cells.
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PMID:Differential in vivo modifications of the HMGI(Y) nonhistone chromatin proteins modulate nucleosome and DNA interactions. 1088 43

Although progress has been made in the understanding of the role of metalloproteinases in tumor progression during metastasis, little is known about their contributions, if any, to tumor formation. Accumulating evidence identified an increased presence of several matrix metalloproteinases in human cancers, but the precise role for interstitial collagenase in tumor formation or progression has not been well defined. Transient induction of collagenase was observed in wild-type mouse skin after treatment with the tumor-promoting agents 12-O-tetradecanoylphorbol-13-acetate (TPA) and chrysarobin, which promote tumorigenesis through protein kinase C-dependent and -independent pathways, respectively. Transgenic mice that constitutively express interstitial collagenase within the epidermis of the skin have an increased susceptibility to tumorigenesis and produced tumors at lower doses of TPA as compared with wild-type mice. Similarly, the transgenic mice showed increased tumorigenesis when promoted with chrysarobin. These results demonstrate that collagenase overexpression can contribute to tumorigenesis via protein kinase C-dependent and -independent pathways. Significantly, compared with wild-type mice, the transgenic mice demonstrated an elevated expression of c-fos in the skin at baseline, before tumor promotion, suggesting a molecular mechanism for the increased tumor susceptibility in collagenase transgenic mice. These findings further support the importance of MMP deregulation in tumorigenesis and suggest that the role of MMP family members is not limited to metastasis but may also contribute to initial tumor development.
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PMID:Collagenase induction promotes mouse tumorigenesis by two independent pathways. 1102 Feb 42

An imbalance between proliferation and apoptosis is important in tumor progression. Endothelin-1 (ET-1) has vasoconstricting and mitogenic activities and may be involved in apoptosis regulation. We found that ET-1 and FasL systems were colocalized in human colon tumors and that ET-1 was secreted by human (HT-29, SW480) and rat (PROb, REGb) colon carcinoma cell lines. Bosentan, a mixed endothelin-A- and -B- (ET(A)/ET(B)) receptor antagonist, potentiated FasL- (APO-1, CD95) induced apoptosis in these cells. The specific inhibition of enzymes involved in ceramide production did not restore survival of cells exposed to FasL and bosentan. Inhibition of PKC with bisindolylmaleimide IX enhanced FasL-induced apoptosis in HT-29, PROb and REGb cells in the absence of bosentan. These results suggest that ET-1 is an autocrine survival factor able to protect colon carcinoma cells against FasL-induced apoptosis, involving the protein kinase C (PKC) but not the sphingomyelin-ceramide signaling transduction pathways.
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PMID:Endothelin receptor blockade potentiates FasL-induced apoptosis in colon carcinoma cells via the protein kinase C-pathway. 1107 19

Trefoil factors (TFFs) are protease-resistant peptides that promote epithelial cell migration and mucosal restitution during inflammatory conditions and wound healing in the gastrointestinal tract. To date, the molecular mechanism of TFFs action and their possible role in tumor progression are unclear. In the present study, we observed that premalignant human colonic PC/AA/C1 and canine kidney MDCK epithelial cells are not competent to invade collagen gels in response to exogenously added TFFs (pS2, spasmolytic polypeptide, and intestinal trefoil factor). In contrast, activated src and RhoA exert permissive induction of invasion by the TFFs that produce similar parallel dose-response curves in src-transformed MDCKts.src and PCmsrc cells (EC50=20-40 nM). Cell scattering is also induced by TFFs in MDCKts.src cells. Stable expression of the pS2 cDNA promotes constitutive invasiveness in MDCKts.src-pS2 cells and human colonic HCT8/S11-pS2 cells established from a sporadic tumor. Furthermore, we found that TFF-mediated cellular invasion is dependent of several signaling pathways implicated in cell transformation and survival, including phosphoinositide PI3'-kinase, phospholipase C, protein kinase C, and the rapamycin target TOR. Constitutive and intense expression of pS2 was revealed by Western blot analyses and immunohistochemistry in human colorectal tumors and their adjacent control mucosa during the neoplastic progression, from the adenoma to the liver metastases. Our studies indicated that TFFs can be involved in cell scattering and tumor invasion via autocrine loops and may serve as potential targets in the control of colon cancer progression.
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PMID:Induction of scattering and cellular invasion by trefoil peptides in src- and RhoA-transformed kidney and colonic epithelial cells. 1115 51

Deregulation of several signaling pathways have been found to be critical for the development of different types of tumors, both in transgenic and spontaneous models. The role of proteases and adhesion molecules during the early stages of tumor progression induced by oncogenes in epithelial and mesenchymal tumors has remained relatively unexplored. This review summarizes recent work showing that different but overlapping signaling effector modules (PKC, v-Ras-RalA-PLD1 or v-Src-RalA-PLD1) induce changes in the production of proteases (uPA and MMPs) and adhesion molecules (fibronectin, CD44, beta 1-integrin) in normal epithelial or mesenchymal cell lines, associated with tumor development in vivo. Overexpression of PKC gamma in normal mammary epithelial cells or of v-Src and v-Ras in NIH3T3 fibroblasts induced in all cases overproduction of uPA and MMPs and a tumorigenic phenotype. Proteases production and tumorigenicity in transformed NIH3T3 cells were dependent on the GTPase RalA. In contrast to the common outcome in protease production by the different tumor promoting stimuli, fibronectin production was high in PKC-overexpressing mammary epithelial cells and it was organized into a rich fibrillar matrix, while oncogene transformed fibroblasts displayed reduced fibronectin production and a total loss of FN fibrillogenesis, an effect also dependent on RalA. These results show that protease overexpression is a common denominator in the acquisition of a malignant phenotype both in mesenchymal and epithelial cells. In contrast there is a dramatic difference in the expression and function of adhesion molecules like fibronectin between these two cell types, suggesting different regulatory roles for this glycoprotein during tumor progression, in cells of different tissular origin.
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PMID:[Signaling pathways regulating the expression of proteases during tumor progression]. 1118 28

A finely tuned Ca(2+) signaling system is essential for cells to transduce extracellular stimuli, to regulate growth, and to differentiate. We have recently cloned CaT-like (CaT-L), a highly selective Ca(2+) channel closely related to the epithelial calcium channels (ECaC) and the calcium transport protein CaT1. CaT-L is expressed in selected exocrine tissues, and its expression also strikingly correlates with the malignancy of prostate cancer. The expression pattern and selective Ca(2+) permeation properties suggest an important function in Ca(2+) uptake and a role in tumor progression, but not much is known about the regulation of this subfamily of ion channels. We now demonstrate a biochemical and functional mechanism by which cells can control CaT-L activity. CaT-L is regulated by means of a unique calmodulin binding site, which, at the same time, is a target for protein kinase C-dependent phosphorylation. We show that Ca(2+)-dependent calmodulin binding to CaT-L, which facilitates channel inactivation, can be counteracted by protein kinase C-mediated phosphorylation of the calmodulin binding site.
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PMID:Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. 1124 24

A physical and functional interaction between the Ca(2+)-binding protein Mts1 (S100A4) and the tumor suppressor p53 protein is shown here for the first time. We demonstrate that Mts1 binds to the extreme end of the C-terminal regulatory domain of p53 by several in vitro and in vivo approaches: co-immunoprecipitation, affinity chromatography, and far Western blot analysis. The Mts1 protein in vitro inhibits phosphorylation of the full-length p53 and its C-terminal peptide by protein kinase C but not by casein kinase II. The Mts1 binding to p53 interferes with the DNA binding activity of p53 in vitro and reporter gene transactivation in vivo, and this has a regulatory function. A differential modulation of the p53 target gene (p21/WAF, bax, thrombospondin-1, and mdm-2) transcription was observed upon Mts1 induction in tet-inducible cell lines expressing wild type p53. Mts1 cooperates with wild type p53 in apoptosis induction. Our data imply that the ability of Mts1 to enhance p53-dependent apoptosis might accelerate the loss of wild type p53 function in tumors. In this way, Mts1 can contribute to the development of a more aggressive phenotype during tumor progression.
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PMID:Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. 1127 47

Recently we showed that partial depletion of mitochondrial DNA (genetic stress) or treatment with mitochondrial-specific inhibitors (metabolic stress) induced a stress signaling that was associated with increased cytoplasmic-free Ca(2+) [Ca(2+)](c). In the present study we show that the mitochondria-to-nucleus stress signaling induces invasive phenotypes in otherwise non-invasive C2C12 myoblasts and human pulmonary carcinoma A549 cells. Tumor-specific markers cathepsin L and transforming growth factor beta (TGFbeta) are overexpressed in cells subjected to mitochondrial genetic as well as metabolic stress. C2C12 myoblasts subjected to stress showed 4- to 6-fold higher invasion through reconstituted Matrigel membrane as well as rat tracheal xenotransplants in Scid mice. Activation of Ca(2+)-dependent protein kinase C (PKC) under both genetic and metabolic stress conditions was associated with increased cathepsin L gene expression, which contributes to increased invasive property of cells. Reverted cells with approximately 70% of control cell mtDNA exhibited marker mRNA contents, cell morphology and invasive property closer to control cells. These results provide insights into a new pathway by which mitochondrial DNA and membrane damage can contribute to tumor progression and metastasis.
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PMID:Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. 1129 24

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