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)

The Hepatitis B Virus X (HBx) protein of hepatitis B virus plays a major role in hepatocellular carcinoma. It has been reported that the mutation and disruption of PTEN, a known tumor suppressor and a negative regulator of phosphatidylinositol 3'-kinase/AKT might be involved in tumor progression. However, the relationship between HBx and PTEN expression in hepatocellular carcinoma (HCC) development is not fully understood. This study reports on an investigation of whether PTEN expression in HBx-transfected cells is modulated by HBx or not. HBx decreased the expression of PTEN in HBx-transfected cells, as evidenced by Western as well as Northern blot analysis. In addition, AKT was found to be activated by HBx, as evidenced by not only the phosphorylation of AKT at serine 473 but by the phosphorylation of the exogenous substrate histone H2B as well, and these were specifically blocked by the presence of wortmannin. Moreover, The growth rate of HBx-transfected liver cells was higher than that of Chang and Chang-pEGFP cells. HBx had no effect on the expression of p53, a known transcriptional activator of PTEN. However, we confirmed that the binding of the p53 protein to p53 binding site-oligo of PTEN promoter is decreased in HBx-transfected liver cells by electrophoretic mobility shift analysis and, in addition, that HBx disrupts p53-mediated PTEN transcription, as evidenced by a PTEN promoter assay. Therefore, we conclude that HBx in liver cells down-regulates the expression of PTEN and activates AKT. This constitutes the first report to demonstrate that HBx has an effect on the p53-mediated transcription of PTEN, which, in turn, is associated with tumor suppression.
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PMID:Hepatitis B Virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells. 1283 24

Small GTPase Rho and its downstream effectors, ROCK family of Rho-associated serine-threonine kinases, are thought to participate in cell morphology, motility, and tumor progression through regulating the rearrangement of actin cytoskeleton. Here we present evidence that transfection of human breast cancer cells with cDNA encoding a dominant active mutant of ROCK causes dispersal of lysosomal vesicles throughout the cytoplasm without perturbing the machinery of the endocytic pathway. The intracellular distribution of lysosomes and endocytosed transferrin, an early endosomal marker, were further assessed by confocal immunofluorescence microscopy. In the active ROCK transfected cells the lysosomal proteins, cathepsin D, LIMPII, and LAMP1, were found throughout the cytoplasm in dispersed small vesicles, which were accessible to the endocytosed Texas Red-labeled transferrin. 3D-image analysis of lysosomal distribution in the active ROCK transfectants revealed abundant punctate signals in the peripheral region of the basal plasma membrane. Cells expressing vector alone did not exhibit these alterations. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, induced LIMPII-positive/ transferrin negative large vacuoles in the perinuclear region, and disappearence of the dispersed small vesicular structures. To our knowledge, this is the first evidence that increasing ROCK expression contributes to selective cellular dispersion of lysosomes in invasive breast cancer cells.
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PMID:Overexpression of ROCK in human breast cancer cells: evidence that ROCK activity mediates intracellular membrane traffic of lysosomes. 1285 12

A balance between proliferation, differentiation, migration and death of cells is critical for the normal development of an organism. Perturbations of this balance can contribute to cancer development. The p21-activated serine/threonine kinases (Paks) play an important role in a variety of cellular functions including cell morphogenesis, motility, survival, angiogenesis, and mitosis. Paks were initially identified as an effector molecules of RHO GTPases; however, recent evidence that they can be activated in both GTPase-dependent and -independent manners expands our understanding of their physiologic functions. Paks play an important role in growth factor signaling, leading to cytoskeletal reorganization that subsequently influences growth factor-mediated cell migration and metastasis functions. Recent findings that Paks play a role in mitosis, nuclear receptor-signaling and deregulation of Pak in cancer cells suggest that these kinases play an important role in both normal development and cancer progression. In this review, we summarize the results of recent advances into the role of Paks in tumorigenesis and metastasis.
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PMID:P21-activated kinases in human cancer. 1288 13

Growth factors and estrogen receptor (ER) signaling cooperate to play essential roles in cell proliferation, differentiation and tumor progression in mouse reproductive organs. Treatment of neonatal mice with diethylstilbestrol (DES) induces an estrogen-independent persistent proliferation and cornification of the vaginal epithelium, which results in cancerous lesions later in life. However, the mechanisms of the estrogen-dependent and -independent pathways essentially remain unknown. We characterized the expression of epidermal growth factor (EGF)-like growth factors (EGF, transforming growth factor alpha (TGF-alpha), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (APR), epiregulin (EPR) and neuregulin (NRG) 1) and erbB receptors (EGF receptor (EGFR), erbB2/neu, erbB3 and erbB4) in the vaginae of mice treated either neonatally (0-4 day) or as adults (55-59 day) with estrogens. EGFR and erbB2 were activated in the vaginal epithelium of mice by estrogen treatment. This activation was also encountered in vaginae from neonatally DES-exposed mice, along with the expression of EGF, TGF-alpha, HB-EGF, BTC, APR, EPR and NRG1. Immunohistochemical analysis indicated that erbB2 was primarily expressed in vaginal epithelium. Finally, we found that serine 118 and 167 located in the AF-1 domain of ERalpha were phosphorylated in these vaginae. AG825, AG1478 or ICI 182,780 administration blocked proliferation of vaginal epithelium induced by neonatal DES exposure. Thus, signal transduction via EGFR and erbB2 could be related to the estrogen-induced vaginal changes and persistent erbBs phosphorylation and sustained expression of EGF-like growth factors, leading to ERalpha activation that may result in cancerous lesions in vaginae from neonatally DES-exposed mice later in life.
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PMID:Estrogen-independent activation of erbBs signaling and estrogen receptor alpha in the mouse vagina exposed neonatally to diethylstilbestrol. 1464 53

Extracellular proteases are recognized as critical factors in the progression of a number of carcinomas, including prostate cancer. Matrix metalloproteases (MMP) are important in processes of tumor growth, invasion and dissemination, but other classes of proteases, such as serine and cysteine proteases, also contribute. We utilized the TRAMP model for prostate cancer to elucidate proteases involved in prostate cancer progression. General proteomic analysis was performed on normal murine prostate, early TRAMP tumors and advanced TRAMP tumors, as well as normal and involved lymph nodes. Zymography and antigenic analyses revealed increased expression of mainly pro-MMP in early TRAMP tumors but substantial elaboration of activated MMP only in late TRAMP tumors. Progressive increase in cysteine, serine and certain membrane-bound proteases from normal to early to advanced prostate tumors, was also seen. Our results implicate pericellular proteases as initiators of major proteolytic cascades during tumor progression and suggest targets for maximal therapeutic effect.
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PMID:Patterns of protease production during prostate cancer progression: proteomic evidence for cascades in a transgenic model. 1466 66

The p53 tumor suppressor is critical for preventing cancer progression. Numerous observations suggest that p53 function can be modulated by the cells' microenvironment. We addressed specifically the impact of cell crowding on the induction of p53 by DNA damage. We report that cell crowding attenuates markedly p53 upregulation, transcriptional activation and subsequent p53-dependent apoptosis following exposure to genotoxic stress. The p53 protein remains short-lived in confluent cultures regardless of the extent of DNA damage, even though it undergoes efficient phosphorylation on the mouse equivalent of human p53 serine 15. This inhibitory effect of cell crowding is not a secondary consequence of density-dependent cell cycle arrest (contact inhibition). Microscopic examination indicates that dense cultures display prominent cadherin-mediated cell-cell junctions, and only poor cell-matrix focal adhesions, whereas sparse cells possess conspicuous matrix adhesions and essentially no cell-cell contacts. High-density cell culture might recapitulate the microenvironment of cells in a living organism, where the response of p53 to DNA damage is reported to be low in some organs and ages. The impact of cell density on p53 activation may have important bearings on the involvement of p53 in tumor suppression and the cellular response to anticancer therapy.
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PMID:Attenuation of the p53 response to DNA damage by high cell density. 1475 47

Grb7 is an adaptor molecule that mediates signal transduction from multiple cell surface receptors to various downstream signaling pathways. Grb7 and its related family member Grb10 and Grb14 share a conserved molecular architecture including an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes a PH domain and shares sequence homology with the Caenorhabditis elegans protein, Mig-10, and a carboxyl-terminal SH2 domain. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues, although the functional significance of such phosphorylation is incompletely understood. Grb7/10/14 family proteins are mainly localized in the cytoplasm, but have been observed at the plasma membrane, focal contacts, or mitochondria under certain conditions. A large number of receptor tyrosine kinases and other signaling molecules can associate with Grb7/10/14 family proteins, mostly through the SH2 domains, although the functional consequences of such interactions have not been well characterized in most cases. Recent studies have suggested that various isoforms of Grb10 play important roles in mediating insulin/insulin-like growth factor regulation of cell proliferation and apoptosis, whereas Grb7 mediates signaling pathways from FAK and EphB1 receptor to regulate cell migration, which is also implicated in tumor progression. This review will discuss the current understanding of Grb7 mediated signal transduction pathways and their role in the regulation of various cellular functions.
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PMID:Grb7 in intracellular signaling and its role in cell regulation. 1476 59

The prolactin (PRL)-dependent rat Nb2 T lymphoma is a valuable model for investigation of molecular mechanisms that underlie tumor progression in hormone-dependent cancers. mRNA differential display was used to screen for novel gene products expressed in hormone-stimulated or differentiating agent-treated Nb2 sublines. From numerous transcripts identified, DNA sequencing and GenBank analysis revealed a novel 289-bp fragment. Using 5'-rapid amplification of complementary ends-PCR, this fragment was used to clone a unique 2117-bp cDNA, designated HRPAP20 (hormone-regulated proliferation-associated protein), in rat lymphoma cells. Computer-assisted sequence analysis revealed a single open reading frame that encoded a putative 20.2-kDa protein. The effect of hormone stimulation to alter expression of HRPAP20 was evaluated by Northern blot analysis of total RNA obtained from PRL-stimulated, lactogen-dependent Nb2-11 cells. Quiescent cells, synchronized in the G(0)-G(1) phase of cell cycle, exhibited reduced HRPAP20 expression compared with exponentially proliferating cultures. The addition of mitogenic concentrations of PRL to stationary cells increased HRPAP20 mRNA accumulation within 4-6 h, corresponding to G(1) cell cycle progression. Immunoblot analysis showed that PRL also increased HRPAP20 protein levels within 4 h. In addition, PRL stimulated serine phosphorylation of the HRPAP20 protein with a similar kinetic pattern. Stable transfection of the HRPAP20 cDNA into Nb2-11 cells significantly (P < 0.01) increased proliferation in the absence of hormonal stimulation and inhibited apoptosis induced by lactogen deprivation (P < 0.001). In the hormone-independent and highly malignant Nb2-SFJCD1 subline, the constitutive expression of HRPAP20 was markedly reduced by exposure of the cells to dietary differentiating agents (butyrate, retinoic acid, and vitamin D(3)). After removal of these substances, PRL stimulated its expression in a manner similar to that observed in PRL-dependent Nb2-11 cells. HRPAP20 expression was also evaluated in MCF-7 cells. Its expression was detectable in quiescent cultures; addition of PRL significantly (P < 0.05) increased HRPAP20 during G(1) cell cycle progression. Exposure of the cells to butyrate or retinoic acid reduced HRPAP20 expression, similar to the effects of these substances in the malignant rat lymphoma. Stable transfection of HRPAP20 into MCF-7 cells significantly (P < 0.006) increased proliferation in the absence of hormone stimulation and augmented survival in the absence of serum (P < 0.05). We conclude that HRPAP20 is a phosphoprotein that is required for proliferation and survival of hormone-dependent tumor cells.
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PMID:Identification of HRPAP20: a novel phosphoprotein that enhances growth and survival in hormone-responsive tumor cells. 1487 33

Tumor microenvironment controls the selection of malignant cells capable of surviving in stressful and hypoxic conditions. The transcription factor, cyclic AMP-responsive element binding (CREB) protein, activated by multiple extracellular signals, modulates cellular response by regulating the expression of a multitude of genes. Previously, we have demonstrated that two cystein residues, at the DNA binding domain of CREB, mediate activation of CREB-dependent gene expression at normoxia and hypoxia. The construction of a dominant-positive CREB mutant, insensitive to hypoxia cue (substitution of two cystein residues at position 300 and 310 with serine in the DNA binding domain) and of a dominant negative CREB mutant (addition of a mutation in serine(133)), enabled a direct assessment, in vitro and in vivo, of the role of CREB in tumor progression. In this work, we demonstrate both in vitro and in vivo that CREB controls hepatocellular carcinoma growth, supports angiogenesis, and renders resistance to apoptosis. Along with the identification, by DNA microarray, of the CREB-regulated genes in normoxia and hypoxia, this work demonstrates for the first time that in parallel to other hypoxia responsive mechanisms, CREB plays an important role in hepatocellular carcinoma tumor progression.
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PMID:A pivotal role of cyclic AMP-responsive element binding protein in tumor progression. 1497 73

Curcumin (diferuloylmethane) is being considered as a potential chemopreventive agent in humans. In vitro it inhibits transcription by NF-kappaB, and the activity of lipoxygenase or cyclooxygenase enzymes, which facilitate tumor progression. In vivo it is protective in rodent models of chemical carcinogenesis. Curcumin contains an alpha,beta-unsaturated ketone, a reactive chemical substituent that is responsible for its repression of NF-kappaB. In compounds other than curcumin this same electrophilic moiety is associated with inactivation of the tumor suppressor, p53. Here we report that curcumin behaves analogously to these compounds. It disrupts the conformation of the p53 protein required for its serine phosphorylation, its binding to DNA, its transactivation of p53-responsive genes and p53-mediated cell cycle arrest.
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PMID:Curcumin impairs tumor suppressor p53 function in colon cancer cells. 1509 Apr 65


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