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)

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with several neoplasia. We present evidence here that the protein EB2, an EBV posttranscriptional activator, has transforming properties not only when expressed in established cell lines such as Rat1 or NIH3T3 but also in primary rat fibroblasts (REF). EB2 transformation in Rat1 cells correlates with an increase in the steady-state level of the cellular oncogenic protein c-Myc, and cotransfection of a plasmid expressing Max suppresses the transformation. These results implicate c-Myc in EB2-mediated cell transformation and help define the pathway by which this EBV early protein causes transformation.
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PMID:The EBV early gene product EB2 transforms rodent cells through a signalling pathway involving c-Myc. 793 54

Stably transfected NIH 3T3-L1 mouse fibroblasts (L1 cells) expressing the simian virus 40 large tumor antigen (LTAg) maintain c-myc expression and proliferation in low serum, whereas cells expressing the mutant form LTAg-K1, defective in binding of the retinoblastoma suppressor gene product pRb, showed reduced levels of c-myc RNA and only background levels of DNA synthesis in low serum. The role of the c-Myc protein in LTAg-induced DNA synthesis was studied in microinjection experiments. Expression of LTAg induced cellular DNA synthesis in > 95% of microinjected serum-starved L1 cells, whereas the mutant LTAg-K1 could not induce DNA synthesis. Coexpression of dominant negative c-Myc or Max mutants with LTAg inhibited DNA synthesis, indicating that functional c-Myc is necessary for induction of DNA synthesis by LTAg. Expression of c-Myc induced programmed cell death (apoptosis) in serum-starved L1 cells. Coexpression of c-Myc with LTAg-K1 restored induction of DNA synthesis without apoptosis. Expression of a truncated LTAg, LTAg-(1-259), defective in binding of the tumor suppressor gene product p53, failed to prevent c-Myc-induced apoptosis. The data indicate that c-Myc can restore the ability of LTAg-K1 to induce DNA synthesis and that LTAg-K1 prevents c-Myc-induced apoptosis in serum-starved L1 cells by its interaction with p53.
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PMID:Role of c-myc in simian virus 40 large tumor antigen-induced DNA synthesis in quiescent 3T3-L1 mouse fibroblasts. 793 65

Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine which is cytotoxic for some tumor cells and transformed cells. The molecular mechanisms which render transformed and tumor cells sensitive to the cytotoxic action of TNF are unclear. We show here that an increased expression of the c-Myc oncoprotein strongly increases cellular sensitivity to TNF cytotoxicity. In Rat1A fibroblasts, which are resistant to TNF, the addition of TNF with a concomitant activation of a hormone-inducible c-Myc-estrogen receptor chimera (MycER) resulted in apoptotic cell death. Similarly, c-Myc overexpression enhanced the sensitivity of NIH3T3 fibroblasts to TNF-induced death. The c-Myc and TNF-induced apoptosis was inhibited by ectopic expression of the Bcl2 oncoprotein and by the free oxygen radical scavenging enzyme Mn superoxide dismutase. Furthermore, in highly TNF-sensitive fibrosarcoma cells, antisense c-myc oligodeoxynucleotides caused a specific inhibition of TNF cytotoxicity. Our results suggest that the deregulation of c-Myc, which is common in human tumors and tumor cell lines is one reason why these cells are TNF sensitive.
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PMID:c-Myc induces cellular susceptibility to the cytotoxic action of TNF-alpha. 795 10

The phosphoprotein c-Myc has the potential to kill cells by apoptosis. To investigate whether c-Myc is involved in tumor necrosis factor alpha (TNF-alpha)-mediated cell killing, we have examined two HeLa cell lines (D98 and H21) which show dramatic differences in their susceptibilities to TNF-alpha cytotoxicity. Northern (RNA) blot analyses showed that there were no significant differences between these cell lines in basal or TNF-alpha-induced mRNA expression for a variety of proteins, including manganous superoxide dismutase, A20 zinc finger protein, plasminogen activator inhibitor type 2, and hsp70, all of which are known to influence the susceptibility of certain cells to TNF-alpha killing. On the other hand, there was a dramatic increase in c-Myc mRNA expression in TNF-alpha-sensitive D98 cells, but not in TNF-alpha-resistant H21 cells, which was only observed when the cells were treated with cycloheximide. Western blot (immunoblot) analyses revealed that even in the absence of TNF-alpha or cycloheximide, c-Myc was detectable only in nuclear extracts of TNF-alpha-sensitive D98 cells, implying a role for preexisting c-Myc in TNF-alpha killing. In support of this interpretation, a c-myc antisense oligonucleotide specifically inhibited the TNF-alpha killing of D98 cells, provided that the oligonucleotide was added 6 h prior to TNF-alpha treatment. Either dexamethasone treatment or transient expression of c-myc antisense cDNA fragments decreased nuclear c-Myc in D98 cells and rendered the cells more resistant to TNF-alpha cytotoxicity. Nuclear c-Myc was also detectable in a TNF-alpha-sensitive human HT-1080 fibrosarcoma cell line, but it was undetectable in a derivative of HT-1080 (SS-HT-1080) known to be resistant to TNF-alpha killing because of overexpression of plasminogen activator inhibitor type 2. HT-1080 cells transfected with antisense c-myc cDNA had significantly less nuclear c-Myc and were resistant to TNF-alpha cytotoxicity. Together, these data indicate that a nuclear transcription factor, c-Myc, plays an important role in sensitizing two different tumor cell types to TNF-alpha cytotoxicity.
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PMID:Nuclear c-Myc plays an important role in the cytotoxicity of tumor necrosis factor alpha in tumor cells. 806 3

The cellular proto-oncogene c-myc is involved in cell proliferation and transformation but is also implicated in the induction of programmed cell death (apoptosis). The same characteristics have been described for the tumor suppressor gene p53, the most commonly mutated gene in human cancer. In quiescent mouse fibroblasts expressing wild-type p53 protein, activation of c-Myc was found to induce apoptosis and cell cycle reentry, preceded by stabilization of p53. In contrast, in quiescent p53-null fibroblasts, activation of c-Myc induced cell cycle reentry but not apoptosis. These results suggest that p53 mediates apoptosis as a safeguard mechanism to prevent cell proliferation induced by oncogene activation.
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PMID:Mediation of c-Myc-induced apoptosis by p53. 809 Dec 32

Glial tumors of all grades and histological types from 72 adults and 48 children were analyzed for mutations of the TP53 gene, loss of heterozygosity (LOH) for 17p, and accumulation of TP53 protein to determine whether the incidence and type of TP53 alterations differ among tumors of different histological type and between tumors from adults and children. These tumors were also evaluated for LOH for chromosome 10 and for amplification of the epidermal growth factor receptor, C-MYC, N-MYC, GLI, platelet-derived growth factor receptor-alpha, and murine double minute 2 genes to determine the patterns of molecular alterations involved in the progression of these neoplasms. Seventeen of the 120 tumors contained mutations of the TP53 gene. One of the tumors with TP53 gene mutation was from one of the 48 patients less than 18 years of age. Twelve of the 17 tumors with mutations occurred among the 27 patients in the 18-45-year age group, while 4 tumors with mutations were among the 45 patients more than 45 years old. There was also an increased incidence of TP53 mutation in patients with anaplastic astrocytoma histology. However, no significant association between presence of TP53 mutation and patient survival was observed. These studies demonstrate that TP53 gene mutations are a common mechanism for glial cell neoplasms in the 18-45-year age group but are unrelated to progression and advanced histological grade. LOH for chromosome 10 and gene amplification, however, occurring in 82 and 40%, respectively, of glioblastoma multiforme, whether seen alone or along with TP53 gene alterations, are related to advanced histological grade of the tumor. In childhood gliomas, in contrast, TP53 gene alterations, LOH for 17p and 10q, and gene amplification are uncommon in tumors of all grades, suggesting that presently unknown mechanisms are responsible for the genesis and progression of these tumors.
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PMID:Alterations of the TP53 gene in human gliomas. 811 23

The product of the c-myc proto-oncogene is an important regulator of cell proliferation and apoptosis in murine fibroblasts. Addition of the tumor promoter, phorbol myristate acetate (PMA), prevents apoptotic cell death induced by low serum concentrations in NIH3T3 cells that constitutively express and are transformed by v-myc. The protective effect of PMA allowed us to analyse the ability of normal c-Myc and Myc deletion mutants to induce serum starved, untransformed NIH3T3 cells to enter S phase. By microinjecting these quiescent cells with wild type and mutant human c-myc plasmids, we showed that full length c-myc is able to induce S phase entry in presence of PMA, but that c-Myc mutants that delete amino acids delta 7/91, delta 41/53, delta 56/103, delta 106/143, delta 265/317 and delta 414/433 are totally inactive. c-Myc did not shorten the period before entry into S phase, since Myc overexpressing cells entered S phase with the same kinetics as control cells when both were stimulated with 20% fetal calf serum (FCS). However, c-Myc overexpression did increase the percentage of cells entering S phase when these cells were stimulated with 2% fetal calf serum. Interestingly, this ability to enhance stimulation by a suboptimal concentration of FCS was retained to a significant degree by Myc mutants that delete amino acids delta 41/53, delta 56/103 or delta 265/317. Finally, Myc mutants that delete delta 106/143 or delta 414/433 exerted a dominant negative effect on S phase entry both in quiescent cells stimulated with 2% FCS and in unsynchronized, cycling cells.
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PMID:Dissection of c-myc domains involved in S phase induction of NIH3T3 fibroblasts. 818 47

In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. This suppression has severe consequences for the recognition of these tumor cells by the immune system of the organism. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription. The transcriptional activity of various HLA-B reporter constructs was tested in a melanoma cell line with low endogenous c-myc expression and in transfectants with high stable and transient c-myc expression. We demonstrated that the responsive region can be mapped to the core promoter region of HLA class I, ruling out any effects of c-myc overexpression on the enhancer A or enhancer B regions. The region subject to downregulation is confined to a 43 base pair fragment encompassing the CCAAT and TATA elements. By coupling this region to a heterologous viral enhancer, we showed that the downmodulation by c-Myc is independent of the presence and nature of an enhancer. These results suggest a mechanism in which c-Myc downregulates the expression of HLA class I genes by interfering with the basal level of transcription.
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PMID:Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements. 820 26

Vitamin K3 is known to inhibit the growth of various rodent and human tumor cells. However, the molecular mechanism of its action is still elusive. We have found that vitamin K3 induces cell cycle arrest and apoptotic cell death in nasopharyngeal carcinoma (NPC) cells, as evaluated by flow cytometry and DNA gel electrophoresis. Involvement of c-fos and c-myc proto-oncogenes and expression of their proto-oncoproteins in VK3-induced cell cycle arrest and apoptosis were also investigated. Northern blot analysis of NPC cells treated with 50 microM VK3 showed that c-fos was transiently induced for 60 min after treatment, while c-myc was persistently induced for 1-9 h after drug treatment. Western blot analysis also showed that c-Fos was induced at 4-6 h and at 1-4 h after treatment with 50 microM and 200 microM VK3 respectively, while c-Myc was induced at 1-6 h and at 4-6 h, respectively, after such treatments. These results suggest that the expression of c-fos and c-myc may play an important role in the signaling mechanism of VK3-induced growth arrest and apoptotic cell death.
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PMID:Vitamin K3-induced cell cycle arrest and apoptotic cell death are accompanied by altered expression of c-fos and c-myc in nasopharyngeal carcinoma cells. 833 46

The product of the c-myc proto-oncogene is an important positive regulator of cell growth and proliferation. Recently, c-Myc has also been demonstrated to be a potent inducer of apoptosis when expressed in the absence of serum or growth factors. To further examine Myc-induced apoptosis, we coexpressed the proto-oncogene bcl2, which has been shown to block apoptosis in other systems, with c-myc in serum-deprived Rat 1a fibroblasts. Here we report that ectopic expression of bcl2 specifically blocks apoptosis induced by constitutive c-myc expression. Constitutive c-myc expression in serum-deprived Rat 1a cells caused a > 15-fold increase in the number of dead cells, accompanied by DNA fragmentation. However, coexpression of bcl2 with c-myc in these cells led to a 10-fold increase in the number of live cells and a significant decrease in DNA fragmentation. Thus, Bcl-2 effectively inhibits Myc-induced apoptosis in serum-deprived Rat 1a fibroblasts without blocking entry into the cell cycle. These results imply that apoptosis serves as a protective mechanism to prevent tumorigenicity elicited by deregulated Myc expression. This protective mechanism is abrogated, however, by Bcl-2 and therefore may explain the synergism between Myc and Bcl-2 observed in certain tumor cells.
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PMID:Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. 845 20


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