Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factors of the Myc/Max/Mad network are important regulators of cell growth, differentiation, and apoptosis and are frequently involved in tumor development. Constitutive expression of v-Myc blocks phorbol ester (TPA)-induced differentiation of human U-937 monoblasts. However, costimulation with interferon-gamma (IFN-gamma) and TPA restores terminal differentiation and G1 cell-cycle arrest despite continuous expression of v-Myc. The mechanism by which TPA + IFN-gamma counteract v-Myc activity has not been unravelled. Our results show that TPA + IFN-gamma treatment led to an inhibition of v-Myc- and c-Myc-dependent transcription, and a specific reduction of v-Myc:Max complexes and associated DNA-binding activity, whereas the steady state level of the v-Myc protein was only marginally affected. In contrast, TPA + IFN-gamma costimulation neither increased the expression of Mad1 or other mad/mnt family genes nor altered heterodimerization or DNA-binding activity of Mad1. The reduced amount of v-Myc:Max heterodimers in response to treatment was accompanied by partial dephosphorylation of v-Myc and c-Myc. Phosphatase treatment of Myc:Max complexes lead to their dissociation, thus mimicking the effect of TPA + IFN-gamma. In addition to modulation of the expression of Myc/Max/Mad network proteins, posttranslational negative regulation of Myc by external signals may, therefore, be an alternative biologically important level of control with potential therapeutic relevance for hematopoietic and other tumors with deregulated Myc expression.
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PMID:Posttranslational regulation of Myc function in response to phorbol ester/interferon-gamma-induced differentiation of v-Myc-transformed U-937 monoblasts. 1033 99

p27Kip1, a cyclin-dependent kinase inhibitor, is a negative regulator of the cell cycle, and apoptosis is a genetically encoded program of cell death. To clarify the relationship between the cell cycle and apoptosis, we investigated expression of p27, cyclin D1 and apoptosis-related proteins (p53, Bax, Bcl-2 and c-Myc) in 60 cases of oral and oropharyngeal squamous-cell carcinoma (SCC) using an immuno-histochemical approach, and evaluated spontaneous apoptosis in vivo. Our most notable finding was that spontaneous apoptosis in the p27-positive group was significantly higher than that in the p27-negative group (p = 0.028). In addition, the percentage of p27-positive cells was clearly correlated with that of Bax-positive cells (gamma = 0.288, p = 0.028) and with that of cyclin D1-positive cells (gamma = 0.416, p = 0.002). Expression of p27 was inversely associated with the clinical stage of total tumor progression (p = 0.027). However, no correlation was found between p27 expression and the following parameters: gender, tumor size, lymph node metastasis, overall survival and disease-free survival. Our results give evidence that the action of the cell-cycle regulator p27 is closely linked with apoptosis in clinical samples from patients and indicate that over-expression of p27 might induce apoptosis in cancer cells through elevation of Bax expression, thereby acting on tumor progression.
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PMID:Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma. 1037 53

Much recent research on c-Myc has focused on how it drives apoptosis. c-Myc is widely known as a crucial regulator of cell proliferation in normal and neoplastic cells, but until relatively recently its apoptotic properties, which appear to be intrinsic, were not fully appreciated. Its death-dealing aspects have gained wide attention in part because of their potential therapeutic utility in advanced malignancy, where c-Myc is frequently deregulated and where novel modalities are badly needed. Although its exact function remains obscure, c-Myc is a transcription factor and advances have been made in characterizing target genes which may mediate its apoptotic properties. Candidate regulators and effectors are also emerging. Among recent findings are connections to the CD95/Fas and TNF pathways and roles for the tumor suppressor p19ARF and the c-Myc-interacting adaptor protein Binl in mediating cell death. In this review I summarize the data establishing a role for c-Myc in apoptosis in diverse settings and present a modified dual signal model for c-Myc function. It is proposed that c-Myc induces apoptosis through separate 'death priming' and 'death triggering' mechanisms in which 'death priming' and mitogenic signals are coordinated. Investigation of the mechanisms that underlie the triggering steps may offer new therapeutic opportunities.
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PMID:Mechanisms of apoptosis by c-Myc. 1037 93

Loss of tumor suppressors that restrain important oncoproteins such as c-Myc may contribute to malignant progression. Bin1 is an adapter protein with features of a tumor suppressor that was identified through its interaction with and inhibition of the oncogenic properties of c-Myc. In this study, we analyzed the patterns of Bin1 expression in normal melanocytes and melanoma cells at different stages of tumor progression. Evidence is provided that Bin1 function is abrogated in melanoma cells by a mechanism based on aberrant splicing of a tissue-specific exon. Specifically, most melanoma cells inappropriately expressed exon 12A, which is spliced alternately into Bin1 isoforms found in brain but not into isoforms found in melanocytes and many other nonneuronal cells. Exon 12A sequences abolished the ability of Bin1 to inhibit malignant transformation by c-Myc or adenovirus E1A. Similarly, these sequences abolished the ability of Bin1 to induce programmed cell death in melanoma cells that endogenously expressed exon 12A. Our findings suggest that aberrant splicing of Bin1 may contribute to melanoma progression, and they define a mechanism by which the activity of a tumor suppressor can be eliminated in cells.
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PMID:Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. 1044 55

Paraneoplastic cerebellar degeneration (PCD) is a disorder in which breast or ovarian tumors express an onconeural antigen termed cdr2, which normally is expressed in cerebellar Purkinje neurons. This leads to an immune response to cdr2 that is associated with tumor immunity and autoimmune cerebellar degeneration. We have found that cdr2, a cytoplasmic protein harboring a helix-leucine zipper (HLZ) motif, interacts specifically with the HLZ motif of c-Myc. Both proteins colocalize in the cytoplasm of adult cerebellar Purkinje neurons, and coimmunoprecipitate from tumor cell lines and cerebellar extracts. cdr2 down-regulates c-Myc-dependent transcription in cotransfection assays, and redistributes Myc protein in the cytoplasm. Disease antisera from six of six PCD patients specifically blocked the interaction between cdr2 and c-Myc in vitro. These data indicate that cdr2 normally sequesters c-Myc in the neuronal cytoplasm, thereby down-regulating c-Myc activity, and suggest a mechanism whereby inhibition of cdr2 function by autoantibodies in PCD may contribute to Purkinje neuronal death.
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PMID:The cytoplasmic Purkinje onconeural antigen cdr2 down-regulates c-Myc function: implications for neuronal and tumor cell survival. 1046 86

The branched-chain amino acid aminotransferase, Bcat1/Eca39, catalyzes the first step of branched-chain amino acid catabolism. Bcat1/Eca39 was originally isolated from a c-myc-induced tumor and was proven to be a direct target for c-Myc regulation. The gene is highly conserved in evolution and disruption of its yeast homolog affects cell growth. To assess the role of Bcat1/Eca39 in mammalian cells, we overexpressed Bcat1/Eca39 in murine cells and studied effects on cell growth. Overexpression of Bcat1/Eca39 had no apparent effect on the proliferation of cells grown with high serum concentrations, but under serum deprivation conditions, led to a decrease in cell viability. Cell death under these conditions displayed apoptotic features. The branched-chain keto acid, alpha-ketoisocaproate, a metabolite of leucine catabolism produced by BCAT1/ECA39, was previously found to inhibit cell growth. We show that alpha-ketoisocaproate can induce rapid apoptotic cell death. This observation suggests that the growth inhibitory effect of BCAT1/ECA39 and its apoptosis promoting effect may be mediated by the levels of the products of BCAT1/ECA39 activity, namely, branched-chain keto acids.
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PMID:Involvement of branched-chain amino acid aminotransferase (Bcat1/Eca39) in apoptosis. 1047 90

In this study, we evaluated the role of the c-myc oncogene in response to cisplatin (DDP) treatment using two melanoma lines derived from the primary tumor (LP) and metastatic lymph node (LM) of the same patient. These cell lines, which retain the phenotypic profile of the original tumors, were studied for growth behavior, expression of c-Myc oncoprotein, and HLA-I antigen. The LM line shows a higher tumorigenic ability, an increased expression of c-Myc protein, and a lack of HLA-I antigen, compared with the LP line. In addition, LP tumor was relatively sensitive to DDP administration, whereas LM tumor was resistant to DDP treatment. To verify whether the increased c-Myc expression observed in the LM line might be responsible for DDP resistance, a c-myc antisense phosphorothioate oligodeoxynucleotide ([S]ODN) was used to down-regulate c-Myc expression. The administration of DDP plus c-myc antisense [S]ODNs produced a decrease in c-Myc protein levels of approximately 50%, accompanied by a tumor weight inhibition of 65%, similar to that obtained when the sensitive line was treated with DDP alone (tumor weight inhibition = 70%). Analysis of apoptosis demonstrated that the sensitivity to DDP of the LP line was related to the ability of tumor cells to undergo apoptosis. Conversely, DDP treatment was not able to induce apoptosis in the LM line, whereas apoptosis was evident both after treatment with c-myc antisense [S]ODNs alone and, more extensively, in combination with DDP. Taken together, these results clearly indicate an important role of c-myc oncogene in the resistance of melanoma to DDP and demonstrate that treatment with c-myc antisense [S]ODN sensitizes a human melanoma line to DDP treatment.
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PMID:Increase of cisplatin sensitivity by c-myc antisense oligodeoxynucleotides in a human metastatic melanoma inherently resistant to cisplatin. 1049 37

E-cadherin expression was previously shown to be activated by RB and c-myc specifically in epithelial cells, through interaction with the AP-2 transcription factor. Here we show that only a wild type c-myc gene, coding for the two c-Myc proteins c-Myc2 and c-Myc1, was able to transactivate the E-cadherin promoter, in contrast to c-Myc2 or c-Myc1 alone which strongly repressed E-cadherin in both epithelial cells and fibroblasts. In addition, overexpression of c-myc2 or c-myc1 inhibited c-myc and RB-mediated activation in a dose-dependent manner, suggesting that the ratio of the two c-Myc proteins is essential for transactivation. We also showed by using several mutants of the E-cadherin promoter, that the AP-2 binding sites were the main target of c-myc2- and c-myc1-mediated repression. AP-2-mediated inhibition was cell-type specific, as was the activation. Nevertheless, when high amounts of c-myc2 and c-myc1 were used, a second c-myc-mediated repression was observed, possibly mediated by the Inr sequence of the E-cadherin promoter. However, this repression was independent of cell type. Our results suggest a new way to regulate c-myc transcriptional activity by interfering with the ratio of the two c-myc proteins, which has already been found to be disrupted in vivo in several tumor types.
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PMID:Opposite transcriptional activity between the wild type c-myc gene coding for c-Myc1 and c-Myc2 proteins and c-Myc1 and c-Myc2 separately. 1052 46

BRCA1 was the first breast cancer susceptibility gene to be identified and cloned. In individuals from high-risk families, mutations in BRCA1 increase the lifetime risk of developing breast cancer eight to tenfold, compared to the general population. How the BRCA1 protein product normally functions to suppress tumor formation and how defects in the gene can ultimately lead to breast cancer have been the focus of intense scrutiny by the scientific and medical communities. BRCA1 has intrinsic transactivation activity and is able to activate the p21 promoter. In addition, BRCA1 is linked to a number of genes involved in transcriptional regulation, including CtIP, c-Myc, the RNA holoenzyme complex, and the histone deacetylase complex. Moreover, BRCA1 is essential for cellular response to DNA damage repair. Inactivation of Brca1 in mouse embryonic stem and fibroblast cells results in increased cell sensitivity to DNA-damaging agents. In human cells, BRCA1 binds to both Rad50 and Rad51 and colocalizes with these proteins at repair foci. Part of BRCA1's response to DNA damage may in fact be corroborated through transcriptional regulation. The expression of GADD45, a DNA damage-responsive gene, is increased immediately after induction of BRCA1. Recently, BRCA1 was shown to repress estradiol (E2)-responsive ER-alpha-mediated transcriptional activity, potentially linking the multiple functions of BRCA1 to specific tissue targets. These recent developments in BRCA1 function are an encouraging step toward understanding the role of BRCA1 in breast cancer formation.
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PMID:Emerging roles of BRCA1 in transcriptional regulation and DNA repair. 1052 24

Transgenic mice expressing the c-Myc oncogene driven by the immunoglobulin heavy chain enhancer (Emu) develop B-cell lymphoma and exhibit a mean survival time of approximately 6 months. The protracted latent period before the onset of frank disease likely reflects the ability of c-Myc to induce a p53-dependent apoptotic program that initially protects animals against tumor formation but is disabled when overtly malignant cells emerge. In cultured primary mouse embryo fibroblasts, c-Myc activates the p19(ARF)-Mdm2-p53 tumor suppressor pathway, enhancing p53-dependent apoptosis but ultimately selecting for surviving immortalized cells that have sustained either p53 mutation or biallelic ARF deletion. Here we report that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that spontaneous inactivation of the ARF-Mdm2-p53 pathway occurs frequently in tumors arising in Emu-myc transgenic mice. Many Emu-myc lymphomas sustained either p53 (28%) or ARF (24%) loss of function, whereas Mdm2 levels were elevated in others. Its overexpression in some tumors lacking p53 function raises the possibility that Mdm2 can contribute to lymphomagenesis by interacting with other targets. Emu-myc transgenic mice hemizygous for ARF displayed accelerated disease (11-week mean survival), and 80% of these tumors lost the wild-type ARF allele. All ARF-null Emu-myc mice died of lymphoma within a few weeks of birth. About half of the tumors arising in ARF hemizygous or ARF nullizygous Emu-myc transgenic mice also overexpressed Mdm2. Therefore, Myc activation strongly selects for spontaneous inactivation of the ARF-Mdm2-p53 pathway in vivo, cancelling its protective checkpoint function and accelerating progression to malignancy.
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PMID:Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. 1054 52


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