Assignment of the feline c-myc gene (MYC) to cat chromosome F2q21.2 by fluorescence in situ hybridization.
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Animals↗
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Host range restrictions of oncogenes: myc genes transform avian but not mammalian cells and mht/raf genes transform mammalian but not avian cells.
The host range of retroviral oncogenes is naturally limited by the host range of the retroviral vector. The question of whether the transforming host range of retroviral oncogenes is also restricted by the host species has not been directly addressed. Here we have tested in avian and murine host species the transforming host range of two retroviral onc genes, myc of avian carcinoma viruses MH2 and MC29 and mht/raf of avian carcinoma virus MH2 and murine sarcoma virus MSV 3611. Virus vector-mediated host restriction was bypassed by recombining viral oncogenes with retroviral vectors that can readily infect the host to be tested. It was found that, despite high expression, transforming function of retroviral myc genes is restricted to avian cells, and that of retroviral mht/raf genes is restricted to murine cells. Since retroviral oncogenes encode the same proteins as certain cellular genes, termed protooncogenes, our data must also be relevant to the oncogene hypothesis of cancer. According to this hypothesis, cancer is caused by mutation of protooncogenes. Because protooncogenes are conserved in evolution and are presumed to have conserved functions, the oncogene hypothesis assumes no host range restriction of transforming function. For example, mutated human proto-myc is postulated to cause Burkitt lymphoma, because avian retroviruses with myc genes cause cancer in birds. But there is no evidence that known mutated protooncogenes can transform human cells. The findings reported here indicate that host range restriction appears to be one of the reasons (in addition to insufficient transcriptional activation) why known, mutated protooncogenes lack transforming function in human cells.
Animals↗
[A study of amplifications of myc gene (c-myc and N-myc) in human ovarian cancer].
Amplifications of myc oncogenes (c-myc, N-myc) were studied by Southern blot hybridization methods in ovarian cancers. Fourteen cases were primary ovarian cancers and one case was metastatic ovarian cancer. Primary and metastatic foci of three primary ovarian cancers were compared. A serous adenocarcinoma had a c-myc gene amplification more than 10 fold without N-myc gene amplification. This case also had an amplification in other c-myc probes with upper and down streams of the second exon. The results suggested that this case had c-myc gene expression. One of these cases had 5 fold amplification of the metastatic focus compared with the primary focus. The amplified c-myc gene did not show relations among clinical courses, prognosis and histologies.
Adult↗
Expression of histone H3 cell cycle-related gene, vimentin and MYC genes in pediatric brain tumors. A preliminary analysis showing the different malignant cell growth potential.
Eleven pediatric brain tumors were studied for the histone H3, Vimentin and MYC gene expression. H3, an S phase cell cycle-related gene (ccr), was found prevalently expressed in tumors with a high mitotic index (MI). Vimentin gene, which contributes to maintaining the cell structure but is also demonstrated to be an early responder gene to growth stimulation was found variously expressed. The different expression of Vimentin gene in the examined samples suggests the active proliferation of the tumor cells. Analysis of MYC gene expression was found increased only in a mesenchymal chondrosarcoma while in other samples MYC mRNA was undetectable. Medulloblastoma, chondrosarcoma, and choroid plexus carcinoma have high S phase H3 gene expression associated with a high MI. Differently an astrocytoma shows a low MI associated with high H3 gene expression. This first preliminary report of H3, Vimentin and MYC gene expression in brain tumors demonstrates that malignant cells are characterized by a different gene expression and different growth potentials.
Adolescent↗
Comparative analysis of the structure and function of the chicken c-myc and v-myc genes: v-myc is a more potent inducer of cell proliferation and apoptosis than c-myc.
To gain a more complete understanding of c-myc regulation in chickens, we have completed the structural characterization of the chicken c-myc gene and have begun to investigate c-myc transcription and protein expression. A comparison of c-myc structure and expression between mammals and birds presents an enigma: there are striking similarities in the pattern of gene expression in the absence of obvious sequence similarities in the controlling elements. We have begun to investigate c-myc and v-myc function using retroviral vectors that differ solely in the Myc proteins that they express. We show that while the overexpression of the smaller c-Myc protein is sufficient to induce morphological transformation in chicken embryo fibroblasts, overexpression of v-Myc provides a stronger signal for cells to enter the cell cycle and is a more potent inducer of apoptosis than c-Myc.
Amino Acid Sequence↗
Amplification of c-myc gene and overexpression of c-Myc protein in breast cancer and adjacent non-neoplastic tissue.
BACKGROUND: Deregulated c-Myc expression and alterations of c-myc oncogene have been reported to play an important role in breast cancer tumorigenesis. We examined the relationship between c-Myc protein level, amplification of c-myc oncogene and commonly used clinical and pathologic factors. METHODS: The studies were conducted on 94 ductal and lobular cancers. Amplification of c-Myc was assessed by the semiquantitative multiplex PCR assay. The amount of c-Myc protein was estimated by the densitometry analysis of Western blots. RESULTS: Amplification of c-Myc was found in 21% of examined cancers. There was no association of c-myc amplification with established risk factors. Overexpression of c-Myc protein without c-myc amplification was associated with negative status of axillary lymph node. The size of lobular carcinoma displaying overexpression of c-Myc and the normal copy number of c-myc gene was significantly smaller than the size of tumor with elevated c-Myc and amplification of c-myc gene (p < 0.01). Within tumors displaying overexpression of c-Myc protein and c-myc gene amplification the size of ductal carcinoma was smaller than the size of lobular carcinoma (p < 0.007). CONCLUSION: Data presented in this study suggest that alterations of c-myc gene and c-Myc protein level might be related to breast cancer progression. The prognostic utility of elevated level of c-Myc protein associated with normal status of c-myc gene for patients with lobular carcinoma requires further studies.
Breast↗
The human myc gene family: structure and activity of L-myc and an L-myc pseudogene.
We have determined the nucleotide sequence and transforming activity of the human L-myc gene and a processed L-myc pseudogene (L-myc psi). We demonstrate by cotransformation assays that a 10.6-kb EcoRI fragment derived from a human placental library contains a complete and functional L-myc gene including transcriptional regulatory sequences sufficient for expression in rat embryo fibroblasts. Organization of the L-myc gene was determined by comparing its sequence to those of the L-myc psi gene and an L-myc cDNA clone derived from a human small cell lung carcinoma. Our results show that L-myc has a three-exon organization similar to that of the c-myc and N-myc genes. The putative L-myc gene product consists of 364 amino acids and contains five of the seven homology regions highly conserved between c-myc and N-myc. These conserved regions are located along the entire length of the putative L-myc protein and are interspersed among nonconserved regions. While the putative L-myc gene product is of a smaller size when compared to the c- and N-myc proteins, the relative positions of certain conserved residues occur in corresponding locations along the peptide backbone of the three proteins. In addition, comparison of the human and murine L-myc gene sequences indicate that the relatively large 5' and 3' untranslated regions are evolutionarily conserved, but that these sequences are totally divergent between the L-, c-, and N-myc genes. Finally, we demonstrate that, like the N- and c-myc genes, the L-myc gene can cooperate with a mutant Ha-ras gene to cause malignant transformation of rat embryo fibroblasts in culture. Our analyses clearly prove that L-myc represents a functional member of the myc oncogene family and further delineate structural features that may be important for the common and divergent functions of the members of this gene family.
Amino Acid Sequence↗
Truncation of exon 1 from the c-myc gene results in prolonged c-myc mRNa stability.
The human c-myc gene consists of three exons transcribed from two distinct promoters and the function of the first, noncoding exon is unknown. In COLO 320 cells, there co-exist normal and truncated (i.e., lacking exon 1) c-myc genes, both of which are transcribed. Studies on the turnover of c-myc mRNA show that the normal mRNA has an in vivo half-life of approximately 30 min which is approximately similar to the turnover time of the mRNA in lymphoblastoid cells. However, the truncated mRNA was found to be substantially more stable. This observation was also made with a Burkitt's lymphoma cell line which has a translocated, truncated c-myc gene. Therefore truncation of the c-myc gene can cause the mRNA to be more stable than the full size product suggesting that this can be a crucial factor in the activation of the c-myc oncogene, by exon 1 loss, in chromosomal translocation. The results also suggest a role for exon 1 in the c-myc mRNA degradative mechanism.
Base Sequence↗
Cleavage arrest in Xenopus embryos injected with a human c-myc gene.
The c-myc protein has been implicated in cell proliferation and differentiation of various cell lines, but its function in early embryos of Xenopus is obscure. We introduced the c-myc gene into embryos using a pcDL-SR alpha plasmid with an efficient promoter of the gene. It was found that fertilized eggs injected with the c-myc gene were arrested at the 4-cell stage within 1 h of the injection, when the plasmid that carried c-myc gene but not the plasmid that carried defective c-myc gene was injected. These results also suggest that Xenopus embryos already have the ability to transcribe an exogenously injected c-myc gene at the 4-cell stage.
Animals↗
A transfected L-myc gene can substitute for c-myc in blocking murine erythroleukemia differentiation.
We investigated the ability of the proto-oncogene L-myc to substitute for c-myc in blocking murine erythroleukemia differentiation. Murine erythroleukemia cells (line C19) were transfected with recombinant plasmids containing genomic and cDNA fragments of the L-myc gene driven by a Moloney murine leukemia virus long terminal repeat. Clones expressing constitutive high levels of L-myc failed to differentiate in response to the chemical inducer N,N'-hexamethylene bisacetamide (HMBA). The block to differentiation correlated with the level of L-myc expression. Furthermore, transfected clones grown in the presence of inducer for an extended period of time showed an increased level of L-myc expression. These results suggest that functional domains of the c-myc gene involved in differentiation are located in the discrete regions of homology between the c- and L-myc genes.
Acetamides↗
Transcription enhancer identified near the human C mu immunoglobulin heavy chain gene is unavailable to the translocated c-myc gene in a Burkitt lymphoma.
In Burkitt lymphoma the c-myc gene, the cellular homologue of the viral oncogene v-myc, has been implicated in the aetiology of this human B-cell malignancy. Burkitt lymphoma cells possess specific chromosomal rearrangements involving the region proximal to the c-myc gene and one of the three human immunoglobulin loci. The nature of the effect exerted by the immunoglobulin loci on the translocated c-myc gene is controversial: whereas some reports have suggested c-myc transcription is elevated in Burkitt lymphoma cells, others have suggested the level of transcription is unaffected by the translation. Recently, transcription enhancer elements have been identified in the intron between the JH and C mu segments of the heavy-chain immunoglobulin gene in mice. If similar enhancers exist in humans they may lead to increased transcription of the translocated c-myc gene and thus contribute to oncogenesis in Burkitt lymphoma. We report here the identification of an enhancer element adjacent to the human C mu gene on normal chromosome 14, but this enhancer does not remain on the abnormal chromosome 14 to which the c-myc gene has been translocated in the Burkitt lymphoma cell line Raji. This element is, therefore, not available for control of the translocated c-myc gene in this case.
Base Sequence↗
Protein kinase C inhibits transcription from the RNA polymerase III promoter of the human c-myc gene.
The c-myc promoter has a unique characteristic showing both RNA polymerase II (pol II) and RNA polymerase III (pol III) activities. Previous studies demonstrated that activating PKC results in upregulation of c-myc expression from its pol II promoter. However, how PKC activation affects expression from the pol III promoter of the c-myc gene is not well understood. This study examines the effect of PKC on the pol III transcription from the c-myc gene by using an in vitro system. We report the inhibition of the c-myc pol III transcript by activating PKC. Further, either a phosphocellulose fraction of HeLa whole cell extract (WCE) enriched for transcription factor TF IIIB, or recombinant TATA-box binding protein could restore the inhibited c-myc pol III transcription under conditions that activate PKC. A role has been proposed for the c-myc pol III transcript in the regulation of c-myc gene expression. Therefore, this report discusses the significance of the downregulation of c-myc expression from its pol III promoter and the possible interplay between the pol II and pol III promoters of this gene.
Cell Fractionation↗
cis activation of the c-myc gene in bovine papilloma virus type 1/human c-myc hybrid plasmids.
The c-myc gene amplification observed in human tumors is likely to represent an activation mechanism aiming at an increased transcription level. In order to evaluate the biological significance of this amplification in the malignant transformation we have designed an experimental model that could possibly mimic this situation in vitro. We have constructed a series of plasmids which physically link the human c-myc gene to the bovine papilloma virus type 1 genome (BPV1) and therefore should be maintained as amplified episomes upon transformation of rodent cells. Anticipating that the high copy number will bring about the immortalizing capacity of the c-myc gene, the constructions were introduced into primary rat embryo cells. Immortal cell lines were established by transfection of the hybrid plasmids carrying either the complete BPV1 genome or the transforming region of the viral genome. The BPV1 DNA alone or the c-myc gene alone has no activity in this assay. The analysis of the established cell lines demonstrates that the transfected plasmids are present not as free copies as anticipated but rather integrated as tandem repeats. We present data which strongly suggest that the immortalization capacity of the hybrid plasmids reflects the activation of the c-myc gene by the transactivable BPV1 enhancer. Although both the BPV1 early genes and the c-myc gene are actively transcribed, most of the cell lines do not display a transformed phenotype.
Animals↗
Bovine papillomavirus type 1-transformed primary mouse fibroblasts show no correlation between tumorigenicity and viral gene expression, but c-myc gene expression is elevated in tumorigenic cell lines.
Bovine papillomavirus type 1 (BPV-1)-transformed primary mouse fibroblasts containing episomal or integrated BPV-1 sequences were analysed for virus-specific transcripts and c-myc gene expression. Total BPV-1-specific expression was high in cell lines containing episomal BPV-1 DNA in comparison to lines containing integrated BPV-1 sequences, mainly due to higher expression of the E6/E7 sequences. No correlation was found between the viral transcription and tumorigenicity, although BPV-1 gene expression occurred in all cell lines. High levels of c-myc expression were found in all cell lines exhibiting a tumorigenic phenotype as compared to the nontumorigenic lines. These data suggest that expression of BPV-1 genes may be essential for transformation but not tumorigenicity, whereas high levels of expression of cellular oncogenes like c-myc may be associated with tumorigenicity.
Animals↗
Novel promoter upstream of the human c-myc gene and regulation of c-myc expression in B-cell lymphomas.
A new promoter of the human c-myc gene called P0, with multiple RNA start sites, was mapped over 500 bases upstream of the two previously identified promoters, P1 and P2. Sequencing full-length cDNA clones of P0 RNAs revealed two open reading frames upstream of that for the P64c-myc protein. P0 RNA is located on polyribosomes and released by puromycin, indicating that it functions as an mRNA. In vitro translation of RNA synthesized from the cloned cDNAs predicts that P0 transcripts are translated into a novel 12.5-kilodalton protein corresponding to the first open reading frame. The regulation of P0 RNA was studied in the B-cell lymphoma cell line Manca, in which only the translocated c-myc allele lacking exon 1 was thought to be active. However, we found that P0 transcription and the DNase I-hypersensitive site associated with this promoter persist on the untranslocated allele, even though P1/P2 transcription as measured by a nuclear runoff assay was repressed. These results suggest that allelic exclusion of c-myc expression in this B-cell lymphoma is caused by a repression of transcription which is specific to the P1/P2 promoters. We previously reported a block to elongation of transcription near the 3' end of exon 1 in the wild-type c-myc gene, which results in an excess of exon 1 over exon 2 transcription (5a). In contrast, we found that in the Daudi B-cell lymphoma, which retains exon 1 in the active allele, equimolar transcription of exons 1 and 2 occurs. This result suggests a model for the activation of c-myc in B-cell lymphomas.
Amino Acid Sequence↗
Mechanism of endogenous myc gene down-regulation in E mu-N-myc tumors.
Transgenic mouse lines carrying the N-myc oncogene deregulated by the immunoglobulin heavy-chain enhancer spontaneously develop B-lymphoid tumors (R. Dildrop, A. Ma, K. Zimmerman, E. Hsu, A. Tesfaye, R. DePinho, and F. W. Alt, EMBO J. 8:1121-1128, 1989; H. Rosenbaum, E. Webb, J. M. Adams, S. Cory, and A. W. Harris, EMBO J. 8:749-755). Permanent cell lines derived from these tumors (E mu-N-myc cell lines) express extremely high levels of the N-myc transgene but little or no detectable endogenous N-myc or c-myc. We have employed nuclear run-on assays to show that down-regulation of endogenous N- and c-myc expression occurs at the transcriptional level. To determine whether the lack of endogenous myc gene transcription is a direct effect of high-level N-myc transgene expression, we have generated Abelson murine leukemia virus (A-MuLV)-transformed cell lines from prelymphomatous E mu-N-myc mice (A-MuLV/E mu-N-myc cell lines). Although these A-MuLV/E mu-N-myc lines express very high levels of the N-myc transgene, they continue to transcribe the endogenous c-myc gene. These findings demonstrate that high-level N-myc gene expression alone does not necessarily lead to down-regulation of endogenous myc gene expression and suggest that events associated with transformation by N-myc may be critical to this process.
Animals↗
Characterization of interleukin-7-induced changes in tyrosine phosphorylation and c-myc gene expression in normal human T cells.
Interleukin-7 (IL-7) is a growth factor involved in regulating lymphopoiesis. We have chosen to study the signal transduction pathway of IL-7 in normal human peripheral blood T lymphocytes. Two early events that occur as a consequence of specific ligand-receptor interaction were examined: activation of protein tyrosine kinases and induction of primary response gene expression. Following treatment of human peripheral blood T cells with IL-7, four cellular proteins with relative molecular weights of 95- (doublet), 105-, and 130-kd were rapidly tyrosine phosphorylated as detected by immunoblotting with an antiphosphotyrosine monoclonal antibody (MAB). The 105-kd tyrosine-phosphorylated protein was membrane-associated after IL-7 stimulation. Treatment of human peripheral blood T cells with IL-7 enhanced expression of the primary response gene c-myc approximately three-fold, as detected by Northern blotting, in the presence or absence of protein synthesis. The rate of c-myc gene transcription increased in the presence of IL-7 and could account for the observed elevation of c-myc RNA levels. In addition, IL-7 treatment induced a slight increase in c-myc message stability. Experiments performed with the protein tyrosine kinase inhibitor genistein and the serine-threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) demonstrated that these kinases were required for IL-7 enhancement of c-myc expression. Treatment with tetradecanoyl phorbol acetate (TPA), a potent activator of protein kinase C (PKC), in combination with IL-7 induced a level of c-myc expression greater than that elicited by either factor alone, suggesting that TPA and IL-7 utilize cooperative signaling pathways to increase c-myc gene expression.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
The N-myc gene product in primary retinoblastomas.
The N-myc gene product in retinoblastomas was examined using the antisera against the N-myc gene product, which was produced as a fusion protein by Escherichia coli. The N-myc gene product was detected not only in the retinoblastoma cell line Y79 but also in primary retinoblastomas as a pair of bands of approximately 62 kilodaltons (KD) by immunoblotting. Immunohistochemical analysis showed positively stained cells with the antibody against the N-myc gene product in a few rosettes or fleuretts containing area of the tumor. The nuclei of the cells were positively stained. The N-myc gene product was not detected in the normal part of the retina or in other parts of the eye. The results suggested that the level of the N-myc gene product may be inversely correlated with the differentiation of retinoblastoma cells and that the detection of the N-myc gene product may be useful in the diagnosis of retinoblastoma. Because the undifferentiated form of retinoblastoma carries a worse prognosis than the differentiated forms, the level of the N-myc gene product may be related to the aggressiveness of the tumor cells. It remains to be seen whether metastatic retinoblastoma has a higher concentration of the N-myc gene product.
Cell Line↗