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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MyoD and c-Myc, members of the large "basic-helix-loop-helix" family of proteins, regulate diverse aspects of both normal and neoplastic growth and specific gene regulation. These two proteins differ at 9 of the 14 amino acids that comprise the basic domains necessary for DNA binding and transcriptional control. Individual amino acids in the MyoD basic domain were mutated to those found at the analogous positions in c-Myc. Four classes of mutants were obtained: (i) those with no effects on MyoD-site binding or activation of MyoD-responsive genes, (ii) those with no effect on MyoD-site binding but with a loss of activation potential, (iii) those with a loss of both DNA binding and activation potential, and (iv) one mutant (mut 9, Leu122----Arg) that left MyoD-site binding unaffected but imparted a new c-Myc-site binding capability. mut 9 competed with wild-type protein for the activation of MyoD-responsive reporter genes but could, like c-Myc, also suppress the adenovirus major-late promoter, which contains a c-Myc binding site. Our studies thus identify specific amino acid residues in the MyoD basic domain that are important for its activity as a DNA-binding transcriptional activator. Most significantly, our results with mut 9 indicate that Leu122 of MyoD is a critical determinant of specific DNA binding and that mutation at this residue can alter this specificity.
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PMID:A point mutation in the MyoD basic domain imparts c-Myc-like properties. 132 87

Hyperparathyroidism is a central component of multiple endocrine neoplasia type 1 (MEN 1), and both sporadic and familial forms of parathyroid disease may share certain pathogenetic features. We recently identified a gene that is clonally rearranged with the PTH locus in a subset of sporadic parathyroid adenomas. This candidate oncogene, PRAD1 (previously D11S287), appears to contribute to parathyroid tumorigenesis in a fashion analogous to activation of C-MYC or BCL-2 by rearrangement with tissue-specific enhancers of the immunoglobulin genes in B-lymphoid neoplasia. The PRAD1 gene maps to 11q13 and has been linked to the BCL-1 breakpoint locus, although not to the most tightly linked MEN 1 markers, by pulsed field gel electrophoresis. PRAD1 may, in fact, be the long-sought BCL-1 lymphoma oncogene. PRAD1 encodes a novel type of cyclin protein and thus may normally function in controlling the cell cycle, perhaps through direct interaction with cdc2 or a related kinase. PRAD1's possible primary, or more likely secondary, involvement in the pathogenesis of MEN 1-related tumors is unknown and under investigation.
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PMID:PRAD1 (cyclin D1): a parathyroid neoplasia gene on 11q13. 148 73

Max and c-Myc proteins, produced in bacteria, were studied for DNA-binding activity using the electrophoretic band-shift assay (EMSA). Both Max homodimers and c-Myc-Max heterodimers selected the same sequence CA(C/T)GTG from an initial pool of 10(6) DNA molecules. From the pool of sequence-specific binding sites, the palindromic site (CACGTG) was preferentially selected over the CATGTG site using two different degenerate oligonucleotide probes. max expression is identical in myc-induced tumor cell lines relative to other cells. Furthermore, max expression is constant in both confluent and serum-stimulated A31 fibroblasts, in contrast to c-myc expression, which is barely detectable in confluent fibroblasts and induced 20-fold by serum growth factors. Based on recognition of the same DNA sequence by Max and c-Myc-Max complexes and differential expression of the two genes, we propose that Max homodimers and c-Myc-Max heterodimers may bind to a common set of cellular target genes.
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PMID:max encodes a sequence-specific DNA-binding protein and is not regulated by serum growth factors. 156 73

Genetic alterations of the c-myc locus in various malignancies and the ability of c-myc to transform cultured cells and induce tumors in transgenic animals attest to its central role in many neoplasms. By dissecting the c-Myc protein, a number of critical functional domains of c-Myc have been identified and characterized; these findings suggest a model for c-Myc function and intracellular activity (Fig. 4). c-Myc is synthesized in the cytoplasm and undergoes oligomerization another protein such as Max. Its nuclear localization signal allows c-Myc to be targeted to and retained in the nucleus, where the protein seeks out and binds to specific DNA sites, perhaps facilitated by c-Myc's ability to bind non-specifically to DNA. Once bound to specific DNA sequences, c-Myc then activates or inhibits transcription of a number of target genes, with consequent alterations in cell growth and differentiation. Continued studies of c-Myc and its partner Max should further elucidate the mechanisms by which c-Myc can contribute both to the regulation of normal cell growth and the alteration in that regulation in neoplasia.
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PMID:c-myc oncoprotein function. 175 43

B-cell malignancies reveal a number of consistent translocations involving the C-MYC, BCL and IG genes. In common, these rearrangements usually lead to an inability of the involved B-cells to respond to normal regulatory controls for expression of the genes. This usually lead to over-production of the protein products of the genes at inappropriate times of the cell growth cycle and appears to allow a survival advantage to the B-cell. The result of these changes almost certainly plays a prominent role in the development of B-cell neoplasia. Classification of these lymphoma's at a molecular level may be of benefit to determine the prognosis and treatment in addition to providing a useful marker of disease. Determining the molecular basis of these B-cell lymphomas may help our understanding of their pathogenesis. This in turn could lead to more rational treatment aimed at altering the abnormal molecular changes and returning the neoplastic cells to normal cell development.
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PMID:Altered gene expression and oncogenesis of B-cell neoplasia. 195 77

The myc protooncogene family has been implicated in cell proliferation, differentiation, and neoplasia, but its mechanism of function at the molecular level is unknown. The carboxyl terminus of Myc family proteins contains a basic region helix-loop-helix leucine zipper motif (bHLH-Zip), which has DNA-binding activity and has been predicted to mediate protein-protein interactions. The bHLH-Zip region of c-Myc was used to screen a complementary DNA (cDNA) expression library, and a bHLH-Zip protein, termed Max, was identified. Max specifically associated with c-Myc, N-Myc, and L-Myc proteins, but not with a number of other bHLH, bZip, or bHLH-Zip proteins. The interaction between Max and c-Myc was dependent on the integrity of the c-Myc HLH-Zip domain, but not on the basic region or other sequences outside the domain. Furthermore, the Myc-Max complex bound to DNA in a sequence-specific manner under conditions where neither Max nor Myc exhibited appreciable binding. The DNA-binding activity of the complex was dependent on both the dimerization domain and the basic region of c-Myc. These results suggest that Myc family proteins undergo a restricted set of interactions in the cell and may belong to the more general class of eukaryotic DNA-binding transcription factors.
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PMID:Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. 200 10

Moloney murine leukemia virus (MoMuLV) is a retrovirus which lacks an oncogene. It is, however, highly oncogenic in rats and mice, in whom it induces thymic lymphomas. These lymphomas are clonal tumors and appear four to six months following virus inoculation. Although provirus integration is random in virus infected non-tumor cells, it shows regional specificity in these tumors, thus suggesting that insertional mutagenesis may play an important role in tumor induction and progression. Our studies have revealed four common DNA regions for provirus insertion in these tumors (Mlvi-1, Mlvi-2, Mlvi-3 and c-Myc), while studies from other laboratories have revealed two additional ones (pvt-1/mis-1 and pim-1). Mlvi-1, Mlvi-2 and Mlvi-3 represent three independent logi since there is no homology between them molecular clones that identify them and they map on different rat chromosomes. It is interesting however that two of them (Mlvi-1 and Mlvi-2), as well as pvt-1/mis-1, map to mouse chromosome 15 which is known to become trisomic in murine thymic lymphomas. In addition to the specificity of provirus integration, tumor induction is also associated with amplification of the proviral DNA. This amplification may be favored during oncogenesis because cells that carry insertion mutations in multiple oncogenes may exhibit growth advantage over cells in which only single insertion mutations have occurred. This could happen because the effect of these mutations may be additive or because there is a synergistic relationship between multiple loci during oncogenesis. This was indeed suggested by the appearance of concerted provirus insertions in Mlvi-1 and Mlvi-2. Alternatively, the amplification of the provirus during tumor induction may be selected because it provides for elevated levels of viral gene products that participate in the process of oncogenesis. Such products may be coded by sequences in the gag/pol region. We indeed present evidence here for a 2 kb tumor specific gag/pol transcript which is expressed in these thymomas. Our analysis of Mlvi-1 and Mlvi-2 has revealed the following. Mlvi-1 contains at least one open reading frame which is conserved among species and which preliminary evidence indicates may be expressed in the thymomas. Additionally Mlvi-1 appears to be present in more than one copy per haploid genome in both rats and humans. In Mlvi-2 we have shown the presence of a transcribed region downstream from the cluster of the integrated proviruses in the MoMuLV induced thymic lymphomas. However this transcript is expressed mostly in rat embryo fibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Oncogenesis by Moloney murine leukemia virus. 359 29

The tumor-suppressor p53 inhibits cell cycle progression by direct transactivation of the p21WAF1/CIP1/SDI1 gene, which encodes a universal inhibitor of cyclin dependent kinases (cdk). The proto-oncogene product c-Myc induces cell cycle progression and, in the absence of survival factors, apoptosis. However, a direct link between the cell cycle machinery and c-Myc has not yet been established. We show that c-Myc has not yet been established. We show that c-Myc abrogates a p53-induced G1-arrest without elevating the expression of cdks or cyclins involved in the G1/S-transition. Instead, the results suggest that c-Myc interferes with the inhibitory action of p21 on cdk/cyclin-complexes by inducing a heat-labile inhibitor of p21. The inactivation of p21 and related cdk-inhibitors may explain several of the oncogenic actions of c-Myc, including the induction of proliferation, immortalisation and the inhibition of differentiation. Modulation of cdk activity by the induction of an inhibitor of cdk-inhibitors represents a novel mechanism of cell cycle regulation in mammalian cells.
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PMID:Abrogation of p53-induced cell cycle arrest by c-Myc: evidence for an inhibitor of p21WAF1/CIP1/SDI1. 747 65

Mouse tissue inhibitor of metalloproteinases-3 (mTIMP-3), a gene specifically not expressed in neoplastic JB6 cells, have been isolated recently through the use of the mRNA differential display technique (Sun, Y., Hegamyer, G., and Colburn, N. H. (1994) Cancer Res. 54, 1139-1144). We report here the full-length mTIMP-3 cDNA sequence, the promoter sequence and partial characterization, expression and induction of TIMP-3, and the possible molecular basis for the lack of mTIMP-3 expression in neoplastic JB6 cells. There are three transcripts arising from alternative polyadenylation of mouse TIMP-3 gene, having sizes of 4.6, 2.8, and 2.3 kilobase pairs, respectively. All three TIMP-3 transcripts are expressed in preneoplastic but not neoplastic JB6 cells. Computer analysis of cloned TIMP-3 promoter revealed six AP-1 binding sites, two NF-KB sites, a c-Myc site, and two copies of a p53 binding motif separated by eight base pairs with two mismatches at the second motif, along with many other cis elements. TIMP-3 gene expression was inducible by AP-1 and NF-KB activators, 12-O-tetradecanoylphorbol-13-acetate, and tumor necrosis factor-alpha only in preneoplastic cells with an induction peak at 2 h post-treatment, suggesting classification of mTIMP-3 as a member of the immediate early gene family. Southern blot, mutational analysis, and transient transcriptional activation experiments revealed that the lack of expression of mTIMP-3 in neoplastic JB6 cells was due neither to gross deletion nor to promoter mutation of the gene, nor was there a lack of transcription factors required for transcriptional activation. Instead, the lack of TIMP-3 expression in neoplastic JB6 cells may reflect an abnormal methylation of the gene. Both hyper- and hypomethylation of the mTIMP-3 gene are associated with complete down-regulation of gene expression in neoplastic JB6 cell lines. Treatment of neoplastic cells with the methylase inhibitor 5-azacytidine caused reexpression of the mTIMP-3 gene in a tumor cell line that showed hypermethylation but not in another that showed hypomethylation of the gene, suggesting a complex role for methylation in the silencing of gene expression.
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PMID:Molecular cloning of mouse tissue inhibitor of metalloproteinases-3 and its promoter. Specific lack of expression in neoplastic JB6 cells may reflect altered gene methylation. 764 7

Numerous studies have demonstrated a critical role for the c-myc gene in the control of cellular growth. Alterations of the c-myc gene have been found associated with many different types of tumors in several species, including humans. The increased synthesis of one of the major forms of c-Myc protein, c-Myc 1, upon methionine deprivation provides a link between the regulation of oncogenes and the nutritional status of the cell. While deregulation or overexpression of the other major form, c-Myc 2, has been shown to cause tumorigenesis, the synthesis of c-Myc 1 protein is lost in many tumors. This suggests that the c-Myc 1 protein is necessary to keep the c-Myc 2 protein "in check" and prevent certain cells from becoming tumorigenic. Indeed, we have shown that overproduction of c-Myc 1 can inhibit cell growth. We have also shown that c-Myc 1 and 2 proteins have a differential molecular function in the regulation of transcription through a new binding site of Myc/Max heterodimers. We have also recently identified new translational forms of the c-Myc protein which we term delta-c-Myc. These proteins arise from translational initiation at downstream start sites which yield N-terminally-truncated c-Myc proteins. Since these proteins lack a significant portion of the transactivation domain of c-Myc, they behave as dominant-negative inhibitors of the full-length c-Myc 1 and 2 proteins. The synthesis of delta-c-Myc proteins is also regulated during cell growth and is repressed by methionine deprivation. Therefore, the synthesis of c-Myc 1 and delta-c-Myc proteins are reciprocally regulated by methionine availability. We have also found some tumor cell lines which synthesize high levels of the delta-c-Myc proteins. Taken together, our data suggest that c-Myc function is dependent on the levels of these different translational forms of c-Myc protein which are regulated by the nutritional status of the cell during growth. Numerous reports have demonstrated a fundamental and diverse role for the myc gene in cellular events, including proliferation, differentiation and apoptosis (Cole 1986; Spencer and Groudine 1991; Askew et al. 1991; Evan et al. 1992). This is dramatically illustrated by the frequent occurrence of a variety of tumors in many species having alterations of myc genes and the transduction of c-myc sequences by retroviruses (Spencer and Groudine 1991).4+ Eisenman 1990).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Methionine deprivation regulates the translation of functionally-distinct c-Myc proteins. 764 22


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