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PubMed1998

Internalization of a Bacillus anthracis protective antigen-c-Myc fusion protein mediated by cell surface anti-c-Myc antibodies.

BACKGROUND: Anthrax toxin, secreted by Bacillus anthracis, consists of protective antigen (PA) and either lethal factor (LF) or edema factor (EF). PA, the receptor-binding component of the toxin, translocates LF or EF into the cytosol, where the latter proteins exert their toxic effects. We hypothesized that anthrax toxin fusion proteins could be used to kill virus-infected cells and tumor cells, if PA could be redirected to unique receptors found only on these cells. MATERIALS AND METHODS: To test this hypothesis in a model system, amino acids 410-419 of the human p62(c-myc) epitope were fused to the C-terminus of PA to redirect PA to the c-Myc-specific hybridoma cell line 9E10. RESULTS: The PA-c-Myc fusion protein killed both mouse macrophages and 9E10 hybridoma cells when administered with LF or an LF fusion protein (FP59), respectively. Similar results were obtained with PA, which suggests that PA-c-Myc used the endogenous PA receptor to enter the cells. By blocking the endogenous PA receptors on 9E10 cells with the competitive inhibitor PA SNKEDeltaFF, the PA-c-Myc was directed to an alternate receptor, i.e., the anti-c-Myc antibodies presented on the cell surface. The c-Myc IgG were proven to act as receptors because the addition of a synthetic peptide containing the c-Myc epitope along with PA SNKEDeltaFF further reduced the toxicity of PA-c-Myc + FP59. CONCLUSION: This study shows that PA can be redirected to alternate receptors by adding novel epitopes to the C-terminus of PA, enabling the creation of cell-directed toxins for therapeutic purposes.

Animals↗
PubMed1989

Localization of amplified c-myc and n-myc in small cell lung cancer cell lines.

In this study 12 small cell lung cancer cell lines were tested for amplification of myc oncogenes, the location of amplified sequences, and the possible correlation between number of dmin and degree of amplification in dmin-containing lines. C-myc appeared to be amplified in four cell lines, and N-myc amplification was detected in two cell lines. No amplification of L-myc was found. The degree of amplification in the different cell lines varied between 20X and 100X. The cell lines with myc amplification appeared to contain numerous dmin, although in one cell line they occurred in only 10% of the cells. The other cells in this line contained a homogeneously staining region (HSR). In situ hybridization was carried out to find the location of the amplification. In four cell llines the amplified myc genes were found to be located on the dmin. In the cell line with the HSR in most cells and dmin in a minority of its cells, amplification was found both at the HSR and on the dmin. In one cell line the myc sequences seemed to be dispersed through the genome. The ratio between the average number of dmin per cell and the degree of amplification did not vary considerably between the cell lines, with one exception. In that cell line the number of dmin exceeded the number of myc sequences by about one order of magnitude. Apparently, the population of dmin in this cell was heterogeneous and amplified myc genes were only present on a subpopulation.

Carcinoma, Small Cell↗
PubMed1986

Genetic alteration of the c-myc protooncogene (MYC) in human primary breast carcinomas.

We have studied the genomic organization of the c-myc locus (MYC) from 121 human primary breast carcinomas. Two types of alterations were observed: (i) the c-myc protooncogene appeared to be amplified 2- to 15-fold in 38 (32%) of the carcinoma DNAs and (ii) a non-germ-line c-myc-related fragment of variable size was detected in 5 primary breast carcinoma DNAs. With three exceptions, all the tumors containing a genetic alteration of the c-myc locus were invasive ductal carcinomas. A significant correlation (P less than 0.02) was observed between patients more than 50 years old and the presence of a genetically altered c-myc. Enhanced levels of c-myc RNA were observed in 10 of 14 breast carcinomas examined. The c-myc gene was genetically altered in 6 of these 10 tumors. The frequency with which the c-myc gene is altered and its correlation with age suggest that it may play a role in the development of breast carcinomas.

Adenofibroma↗
PubMed1985

V-myc- and c-myc-encoded proteins are associated with the nuclear matrix.

A series of extraction procedures were applied to avian nuclei which allowed us to define three types of association of v-myc- and c-myc-encoded proteins with nuclei: (i) a major fraction (60 to 90%) which is retained in DNA- and RNA-depleted nuclei after low- and high-salt extraction, (ii) a small fraction (1%) released during nuclease digestion of DNA in intact nuclei in the presence of low-salt buffer, and (iii) a fraction of myc protein (less than 10%) extractable with salt or detergents and found to have affinity for both single- and double-stranded DNA. Immunofluorescence analysis with anti-myc peptide sera on cells extracted sequentially with nucleases and salts confirmed the idea that myc proteins were associated with a complex residual nuclear structure (matrix-lamin fraction) which also contained avian nuclear lamin protein. Dispersal of myc proteins into the cytoplasm was found to occur during mitosis. Both c-myc and v-myc proteins were associated with the matrix-lamin, suggesting that the function of myc may relate to nuclear structural organization.

Animals↗
PubMed1986

Features of the chicken c-myc gene that influence the structure of c-myc RNA in normal cells and bursal lymphomas.

The chicken c-myc gene is the target for proviral insertion mutations in bursal lymphomas and has been transduced to generate several viral oncogenes, but the boundaries of its exons have not been securely established. To define the landmarks of the chicken c-myc gene necessary to produce its mRNA, we used an RNase protection assay and a cDNA clone to analyze the c-myc mRNAs from normal chicken embryos and from two bursal lymphomas: LL6, which contains an avian leukosis virus provirus downstream of the c-myc coding region, and LL7, which contains an avian leukosis virus provirus upstream of the c-myc coding region. Two initiation sites for normal c-myc mRNA are less than 7 bases apart, downstream of a GC-rich region lacking canonical TATA and CAAT sequences. The first exon has two open reading frames for the entire length but no initiator methionine codons. The splice donor and acceptor sites at the boundary of the first intron were assigned by comparing a sequence of an LL6 c-myc cDNA clone with a genomic DNA sequence and confirmed by RNase protection of labeled RNA probes by normal and LL6-derived mRNAs. Two potential polyadenylation signals are located approximately 250 and 400 bases downstream of the c-myc coding region in the third exon, but only the more distal signal is utilized in both normal cells and the LL7 tumor. The proviral integration in the LL6 tumor occurred upstream of the authentic c-myc polyadenylation signal accounting for polyadenylation of this transcript in the proviral long terminal repeat.

Animals↗
PubMed2001

Translocations involving c-myc and c-myc function.

c-MYC is the prototype for oncogene activation by chromosomal translocation. In contrast to the tightly regulated expression of c-myc in normal cells, c-myc is frequently deregulated in human cancers. Herein, aspects of c-myc gene activation and the function of the c-Myc protein are reviewed. The c-myc gene produces an oncogenic transcription factor that affects diverse cellular processes involved in cell growth, cell proliferation, apoptosis and cellular metabolism. Complete removal of c-myc results in slowed cell growth and proliferation, suggesting that while c-myc is not required for cell proliferation, it acts as an integrator and accelerator of cellular metabolism and proliferation.

Basic-Leucine Zipper Transcription Factors↗
PubMed1992

An embryonically expressed gene is a target for c-Myc regulation via the c-Myc-binding sequence.

We have used a subtraction/coexpression strategy involving two different tumors derived from c-myc-bearing transgenic mice to identify a gene that is a target for c-Myc regulation. The gene, expressed in certain embryonic and adult tissues and in several (but not all) c-myc-based tumors, bears a functional c-Myc-binding sequence located 3' to its transcription start site. This sequence is required for the binding of a nuclear protein complex which, by antibody analysis, includes c-Myc. This site is also required for expression of a reporter gene in chimeric constructs transfected into c-myc-overexpressing cells and, conversely, requires c-myc cotransfection for its enhanced expression in COS cells. Furthermore, transfection of c-myc blocks the normal down-regulation of this gene, which occurs in embryonic stem cells as they undergo differentiation. This target gene encodes an anonymous cDNA (ECA39) found previously to be amplified in a teratocarcinoma cell line.

Animals↗
PubMed1991

An avian retrovirus expressing chicken pp59c-myc possesses weak transforming activity distinct from v-myc that may be modulated by adjacent normal cell neighbors.

We demonstrate that EF168, an avian retrovirus that expresses the chicken pp59c-myc proto-oncogene, transforms quail embryo fibroblasts in vitro. An EF168-transformed quail clone, EF168-28, containing a single provirus, synthesizes several hundred copies of c-myc RNA and expresses elevated levels of the pp59c-myc gene product. The EF168 provirus in EF168-28 was isolated as a molecular clone, and the nucleotide sequence of its c-myc allele was confirmed as identical to that of exons 2 and 3 of the chicken c-myc proto-oncogene. Extended infection of quail embryo fibroblast cultures with EF168 induced a number of in vitro transformation-associated parameters similar to those elicited by the oncogenic v-myc-encoding retrovirus MC29, including alteration of cellular morphology, anchorage-independent growth, and induction of immortalized cell lines. Despite the fact that EF168 and MC29 shared these biological activities, further analysis revealed that EF168 initiated transformation in quail embryo fibroblasts, bone marrow, or adherent peripheral blood cultures 100- to 1,000-fold less efficiently than did MC29. Further, in contrast to MC29-induced foci, EF168 foci were smaller, morphologically diffuse, and less prominent. Analysis of newly infected cells demonstrated efficient expression of EF168 viral RNA in the absence of transformation. These differences suggest that while the pp59v-myc gene product can exert dominant transforming activity on quail embryo fibroblasts, its ability to initiate transformation is distinct from that of the pp110gag-v-myc gene product encoded by MC29 and may be suppressed by adjacent nontransformed cell neighbors.

Animals↗
PubMed2005

C-Myc-independent restoration of multiple phenotypes by two C-Myc target genes with overlapping functions.

C-MYC, a transforming oncogene that is frequently overexpressed in many human cancers, regulates a variety of normal functions including cell cycle progression, apoptosis, and maintenance of cell size, morphology, and genomic integrity. Many target genes are modulated by c-Myc, and some can recapitulate a limited number of the above functions. Because most of these have been assessed in cells which also express endogenous c-Myc, however, it is not clear to what extent its proper regulation is also required. We show here that, in c-Myc nullizygous cells, two direct target genes, MT-MC1 and HMG-I, could each recapitulate multiple c-Myc phenotypes. Although these differ somewhat for the two genes, substantial overlap and cooperativity exist. The enforced expression of these two genes was also associated with the differential deregulation of some previously described c-Myc target genes, indicating the presence of a complex molecular circuitry. These observations argue that, despite the great diversity of gene regulation by c-Myc, many, although not all, of its functions can be phenocopied by a small subset of key downstream target genes. The approach described here should permit the identification of other target genes capable of further c-Myc-independent complementation.

Animals↗
PubMed2001

Use of a modified ornithine decarboxylase promoter to achieve efficient c-MYC- or N-MYC-regulated protein expression.

One of the advantages of viral-directed enzyme prodrug therapy (VDEPT) is its potential for tumor-specific cytotoxicity. However, the viruses used to deliver cDNAs encoding prodrug-activating enzymes transduce normal cells as well as tumor cells, and several approaches to achieve tumor-specific expression of the delivered cDNAs are being investigated. One such approach is to regulate transcription of the prodrug-activating enzyme with a promoter that is preferentially activated by tumor cells. Published data suggest that the most promising transcription factor/promoter/enhancer combinations are those activated by a tumor-specific transcription factor to retain tumor cell specificity but that are equal in strength to nonspecific viral promoters in their ability to up-regulate target cDNAs. This report identifies MYC-responsive, modified ornithine decarboxylase (ODC) promoter/enhancer sequences that up-regulate target protein expression in tumor cells overexpressing either N-MYC or c-MYC protein. The most efficient of the four constructs assessed contained six additional CACGTG MYC binding sites 5' to the endogenous ODC promoter (R6ODC). Reporter assays with this chimeric promoter/enhancer regulating expression of chloramphenicol acetyltransferase demonstrated 50-250-fold more activity in MYC-expressing cells compared with similar assays with promoterless plasmids. The R6ODC regulatory sequence was approximately equivalent to the CMV promoter in inducing expression of the neomycin resistance gene in c-MYC-expressing SW480 and HT-29 colon carcinoma cells and in N-MYC-expressing NB-1691 neuroblastoma cells. The modified ODC promoter may, therefore, be useful in achieving tissue-specific expression of target proteins in tumor cells that overexpress c- or N-MYC.

Animals↗
PubMedDate not supplied

[MYC protein and proteins antigenically related with MYC in acute lymphoblastic leukemia].

The gross structure and the expression of the c-myc oncogene were analyzed in primary cells from 15 acute lymphoblastic leukemia patients. Southern blot analysis was used to detect possible alterations in the structure of this gene. Alterations (rearrangement and/or amplification) were observed in seven of the 15 samples studied. When the expression of MYC protein was evaluated by Western blot analysis, we found no correlation between c-myc gene alterations and p67 c-myc, which was expressed in the 15 samples studied. The analysis of expression also revealed various MYC-related proteins (115, 110 and 60 kD). These proteins were expressed at variable levels in all leukemic cells, other transformed cells, and in normal peripheral blood lymphocytes (PBL) induced to proliferate with interleukin 2. We detected the 110 kD and 40 kD MYC-related proteins in fresh normal PBL and in samples from patients in complete remission. These studies indicate that the c-myc alterations and protein expression are unrelated to percentage of leukemic blasts, cell morphology or immunophenotype. Our work shows that the expression of MYC-related proteins from 115, 60 and 40 kD is associated with mechanisms of cell activation, and perhaps these proteins may play a role in cellular proliferation-transformation.

Genes, myc↗
PubMed1995

A divergent cDNA homologue of the c-myc proto-oncogene in the eastern oyster Crassostrea virginica: implications for Myc evolution.

The polymerase chain reaction was used to identify myc-like cDNA fragments from several marine invertebrate phyla. A PCR clone produced from the eastern oyster Crassostrea virginica was subsequently used to screen a larval cDNA library, and a 1.9-kb cDNA clone was isolated and sequenced. The putative amino acid sequence encoded by this clone evidences a leucine zipper at its predicted carboxyl-terminus and has an overall structural similarity to vertebrate c-myc proto-oncogenes with several regions of high amino acid similarity. However, this oyster cDNA clone lacks the necessary amino acid conservation in the critical functional domains of Myc and thus is unlikely to function intracellularly in the oyster as a true homologue of vertebrate c-myc. We propose that the oyster cDNA clone described here represents a gene that has been derived from the same ancestral gene that eventually gave rise to vertebrate c-myc. Despite the apparent critical importance of the c-myc proto-oncogene in regulating cellular activities, these data suggest that the c-myc gene: (1) is unique to deuterostome phyla, and (2) assumed its critical role in regulating cell cycle activities at the divergence of the deuterostome ancestors from other protostomes during the Cambrian explosion. In support of these conclusions we present a functional model for the evolution of the Myc gene.

Amino Acid Sequence↗
PubMed1994

Lack of correlation between N-myc and MAX expression in neuroblastoma tumors and in cell lines: implication for N-myc-MAX complex formation.

Detectable levels of MAX messenger RNA were found in a set of human neuroblastoma tumors and established cell lines. MAX mRNA levels were independent of tumor stage and N-myc genomic amplification. By contrast, N-myc mRNA transcripts were detectable only in tumors with amplification of N-myc gene and in cell lines. Analysis by reverse transcriptase polymerase chain reaction and hybridization to specific oligodeoxynucleotide probes revealed approximately equal amounts of two MAX transcripts in all cases analyzed. Immunoprecipitations with a specific antibody to MAX detected two proteins of M(r) 21,000 and 22,000 in approximately equal amounts in all neuroblastoma lines regardless of N-myc amplification and/or expression. On the other hand, protein binding to the myc DNA consensus sequence correlated with N-myc expression in neuroblastoma cells. Thus, N-myc expression might be a limiting factor in the formation of the N-myc-MAX heterodimer in neuroblastomas.

Amino Acid Sequence↗
PubMed1997

Upregulation of endogenous p53 and induction of in vivo apoptosis in B-lineage lymphomas of E(mu)-myc transgenic mice by deregulated c-myc transgene.

E(mu)-myc transgenic mice carry a constitutively overexpressed c-myc oncogene and develop B-lineage lymphomas. Previous studies have shown that c-myc overexpression can lead to in vitro apoptosis. Here, we investigated the in vivo effects of altered c-myc expression on cell proliferation versus death in spontaneously arising E(mu)-myc tumors. E(mu)-myc tumors display extensive in vivo apoptosis confined to small clusters of cells with greatly increased expression of both the c-myc transgene and the endogenous p53 gene as compared with that in normal, pretumor, or surrounding tumor tissue. This restricted overexpression of both the c-myc transgene and the endogenous p53 gene in small clusters of apoptotic tumor cells indicates that overexpression of these genes and apoptosis are not obligatory or uniform during tumor development and suggests that further somatic mutations or microenvironmental influences may be responsible for these properties. Nevertheless, the clear ability of tumor cells to undergo apoptosis in vivo may be exploitable for therapeutic purposes.

Animals↗
PubMed2000

Expression of N-myc and MRP genes and their relationship to N-myc gene dosage and tumor formation in a murine neuroblastoma model.

BACKGROUND: Although the association between N-myc gene amplification and poor clinical outcome in neuroblastoma is well established, the mechanism by which amplification influences prognosis is not well defined. PROCEDURE: We used a human N-myc transgenic mouse model to investigate the role of N-myc in neuroblastoma, including its relationship to the multidrug-resistance-associated protein (MRP) gene. We developed a rapid real-time PCR method to distinguish homozygous and hemizygous N-myc mice that is comparable to Southern analysis. RESULTS: A highly significant correlation (P < 0.0001) between N-myc and MRP expression was demonstrated in murine tumors. Amplification of the transgene was observed in the majority of tumors, highlighting the clinical relevance of this model. However, no correlation between N-myc expression and transgene dosage or tumor latency was observed. CONCLUSIONS: The data suggest that increased N-myc dosage contributes to increased tumor incidence and decreased latency by mechanisms independent of N-myc expression.

ATP-Binding Cassette Transporters↗
PubMed2007

Oligopeptides impairing the Myc-Max heterodimerization inhibit lung cancer cell proliferation by reducing Myc transcriptional activity.

Deregulated CMYC gene causes cell transformation and is often correlated with tumor progression and a worse clinical outcome of cancer patients. The transcription factor Myc functions by heterodimerizing with its partner, Max. As a strategy to inhibit Myc activity, we have synthesized three small peptides corresponding to segments of the leucine zipper (LZ) region of Max. The purpose of these peptides is to occupy the site of recognition between Myc and Max located in the LZ and inhibit-specific heterodimerization between these proteins. We have used the synthesized oligopeptides in two lung cancer cell lines with different levels of Myc expression. Results demonstrate that: (i) the three peptides resulted equally effective in competing the interaction between Myc and Max in vitro; (ii) they were efficiently internalized into the cells and significantly inhibited cell growth in the cells showing the highest Myc expression; (iii) one specific peptide, only nine aminoacids long, efficiently impaired the transcriptional activity of Myc in vivo, showing a more stable interaction with this protein. Our results are relevant to the development of novel anti-tumoral therapeutic strategies, directed to Myc-overexpressing tumors.

Amino Acid Sequence↗
PubMed1995

Reversal of alcohol's effects on neurite extension and on neuronal GAP43/B50, N-myc, and c-myc protein levels by retinoic acid.

Alcohol teratogenesis may be due in part to inhibition of neuronal differentiation by ethanol. We showed previously that alcohol decreased neuronal differentiation (neurite extension) and increased N-myc and c-myc neuronal protein levels. Since Growth-Associated Protein 43 (GAP43/B50) levels must increase for neurons to differentiate, alcohol may decrease GAP43/B50. Alcohol dose-dependently (0-0.5%) decreased GAP43/B50 protein levels by up to 92% in immature LA-N-5 cells. Five nM retinoic acid alone induced differentiation and increased GAP43/B50 levels to 230% of control. These retinoic acid-induced increases in GAP43/B50 and neurite outgrowth, and decreases in N-myc and c-myc, were reversed dose-dependently by alcohol (0-0.5%). Conversely, the adverse effects of 0.25% alcohol on neurite extension, GAP43/B50, N-myc, and c-myc were prevented by 15 and 45 nM retinoic acid. These results suggest that inhibition of neuronal differentiation by alcohol and prevention of such effects by retinoic acid are related to changes in GAP43/B50, N-myc and c-myc.

Cell Differentiation↗
PubMed1992

L-myc and N-myc influence lineage determination in the central nervous system.

The N-myc and the L-myc proto-oncogenes are expressed during embryonal development mainly in the developing brain. Studies of their expression in single neuroepithelial cells revealed that neural precursors not yet committed to the glial or the neuronal lineage expressed both genes, but after lineage commitment they expressed either N-myc or L-myc. Moreover, enforced expression of L-myc in the neural precursor cell line 2.3D caused neuronal differentiation, while the expression of N-myc promoted glial differentiation. These results indicate that L-myc and N-myc play critical roles in lineage determination for the central nervous system.

Animals↗