Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “MYC”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources
PubMed2000

Ubiquitylation and destruction of endogenous c-mycS by the proteasome: are myc boxes dispensable?

c-MycS proteins are truncated forms of the transcription factor which have been shown to be produced by translation initiation at internal methionines (101, 121, and 134) and to be functional in the regulation of gene expression, cell proliferation, and apoptosis. Treatment of human leukemia HL60 cells with lactacystin, a specific inhibitor of the proteasome, increased the steady-state levels of endogenous c-MycS proteins. The half-life of endogenous [(35)S]MycS was similar to that of c-Myc ( approximately 23 min) in HL60 cells. c-Myc(Delta2-143), which lacks the transcription regulatory domain, had a half-life which was similar to that of endogenous c-Myc in 293 and HL60 cells. Treatment of the cells with lactacystin stabilized [(35)S]Myc(Delta2-143) and [(35)S]Myc and caused multi-ubiquitin conjugates of c-Myc, c-MycS, and Myc(Delta2-143) to accumulate. These findings indicate that the Myc homology boxes and the rest of the transcription regulatory domain (the first 144 amino acids) are dispensable for ubiquitylation and rapid destruction of c-MycS and c-Myc by the proteasome.

Acetylcysteine↗
PubMed1999

N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant.

To identify genes regulated by N-myc, subtraction of whole embryo cDNA was carried out between wild type and N-myc-deficient mutant mice. Six cDNA clones were isolated as representing genes expressed higher in the mutant embryos and two as those expressed lower. One of them, Ndr1, coding for 43 kDa cytoplasmic protein was studied in detail. The Ndr1 gene was augmented 20-fold in the mutant embryos at 10.5 days post coitus which is indicative of repression by N-myc. An inverse relationship actually existed between the expression of N-myc and Ndr1 in various developing tissues of the wild type embryos. In the early stage of differentiation of these tissues when N-myc expression was high Ndr1 expression was low or undetectable, and later when N-myc activity diminished Ndr1 expression was augmented concomitantly with the occurrence of terminal differentiation. To establish the direct link between N-myc activity and the Ndr1 regulation, the Ndr1 gene was cloned and analyzed. The Ndr1 promoter activity was down-regulated by N-myc, and more strongly by the combination of N-myc and Max in the cotransfection assay. This repressive effect was mediated by the promoter region within 52 base pairs from the transcription start site but direct binding of N-myc:Max to the promoter sequence was not demonstrated, which is analogous to the cases recently reported for transcriptional repression by c-myc. c-myc also repressed Ndr1 promoter activity similarly to N-myc. The effect of N-myc:Max was sensitive to Trichostatin A, indicating involvement of histone deacetylase activity in repression of the Ndr1 promoter. The strategy we adopted in identifying target genes of a transcription factor should prove widely applicable when mutant animals are available.

Amino Acid Sequence↗
PubMed2003

The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or c-myc.

A major prognostic marker for neuroblastoma (Nb) is N-myc gene amplification, which predicts a poor clinical outcome. We sought genes differentially expressed on a consistent basis between multiple human Nb cell lines bearing normal versus amplified N-myc, in hopes of finding target genes that might clarify how N-myc overexpression translates into poor clinical prognosis. Using differential display, we find the previously described growth-inhibitory gene Ndrg1 is strongly repressed in all tested Nb cell lines bearing N-myc amplification, as well as in a neuroepithelioma line with amplified c-myc. Overexpression of N-myc in non-amplified Nb cells leads to repression of Ndrg1, as does activation of an inducible c-myc transgene in fibroblasts. Conversely, N-myc downregulation in N-myc-amplified Nb cells results in re-expression of the Ndrg1, and stimuli known to induce Ndrg1 do so in Nb cells while simultaneously down-regulating N-myc. Relevant to these results, we demonstrate an in vitro interaction of Myc protein with the Ndrg1 core promoter. We also find that Ndrg1 levels increase dramatically during in vitro differentiation of two cell lines modeling neural and glial development, while c- and N-myc levels decline. Our results combined with previous information on the Ndrg1 gene product suggest that downregulation of this gene is an important component of N-Myc effects in neuroblastomas with poor clinical outcome. In support of this notion, we find that re-expression of Ndrg1 in high-Myc Nb cells results in smaller cells with reduced colony size in soft-agar assays, further underscoring the functional significance of this gene in human neuroblastoma cells.

Agar↗
PubMed2000

N-Myc shares cellular functions wiht c-Myc.

N-Myc is a member of the myc family of proto-oncogenes involved in initiation and progression of tumors. While c-MYC, the most characterized member of the family, is well known for its role in cellular proliferation and apoptosis, the function of N-MYC in differentiation and proliferation remains unclear. N-Myc mutant mice present a phenotype more consistent with a role of N-MYC protein in proliferation of precursor populations than in differentiation per se. Recent studies have also shown that N-MYC can enhance apoptosis and shorten the G1 phase of the cell cycle. However, the role of N-MYC in instigating cell-cycle progression has not been clearly demonstrated. Here, we demonstrate that overexpression of N-myc or activation of inducible N-MYC proteins is sufficient to induce apoptosis in serum-starved fibroblast cells, an effect that can be counteracted by overexpression of Bcl-2. Moreover, N-MYC can induce the reentry of quiescent cells into the cell cycle even in the absence of external stimuli. These results indicate that N-MYC and c-MYC share many properties, supporting the model that MYC-specific roles during embryonic development are mediated, at least in part, via their specific profile of expression rather than by their different protein functions.

Animals↗
PubMed1991

Activation of c-myc promoter by c-myc protein in serum starved cells.

The function of the c-myc protein, the product of a proto oncogene, is not clearly understood although many reports, including ours, suggest that the c-myc protein plays several roles in the regulation of transcription and DNA replication. Here we examined the effects of c-myc protein on transcription from the c-myc promoter, and by inference its role in auto-regulation, after introducing into cultured cells a c-myc expression vector and a CAT reporter gene linked to the promoter and upstream region of the human c-myc gene. To minimize the effects of the endogenous c-myc protein on the exogenously added CAT reporter gene, the transfected cells were treated under serum-free conditions. The results show that CAT expression from the myc promoter increased in a dose-dependent manner after addition of the c-myc expression vector, and that it also required the presence of a c-myc binding sequence previously identified 2 kb upstream from c-myc's first exon. Moreover, the domains of the c-myc protein important for transactivation were determined by use of various deletions mutants of c-myc cDNA. The results showed that the N-terminal portion in the c-myc protein was necessary for transactivation beside the C-terminal portion containing basic region, helix-loop-helix, and leucine zipper.

3T3 Cells↗
PubMed1991

A comparative analysis of N-myc and c-myc expression and cellular proliferation in mouse organogenesis.

The distribution of c-myc and N-myc transcripts during mouse organogenesis was investigated by in situ hybridization and compared to proliferation in several tissues. Only c-myc expression was found during the formation of cartilage, brown adipose tissue, glandula submandibularis, thymus and liver. There was a temporally and spatially ordered expression of N-myc only during the organogenesis of brain, retina and eye lens. In some organs (e.g., in lung and tooth bud), c-myc and N-myc were expressed in a striking complementary pattern that reflected the ontogenic origins of different tissue components. Transcripts of both genes were found in the early gut epithelium, but as formation of villi began, the spatial expression pattern of N-myc and c-myc diverged. The results suggest a link between the proliferative state of cell types and the differential expression of N-myc vs. c-myc. Specifically, c-myc is only expressed in rapidly proliferating tissues, while N-myc expression often persists through cytodifferentiation, e.g., during development of eye lens, retina, telencephalon and gut epithelium. Thus, in spite of the structural similarities of N-myc and c-myc genes and proteins their developmental expression patterns suggest different functional roles.

Animals↗
PubMed2006

B-myc: N-terminal recognition of myc binding proteins.

B-Myc is an endogenous, N-terminal homologue of transcription factor c-Myc that lacks the C-terminal DNA binding and protein dimerization domain of c-Myc. Clinical mutations in the c-Myc N-terminal region, and the subsequent misregulation of Myc, are implicated in the development of numerous human cancers. Myc functions to both activate and repress transcription by associating with multiple binding partners. We investigated the structural and dynamical properties of B-Myc, free or associated with the transactivation inhibitor, MM-1, and the activator, TBP, using NMR spectroscopy. B-Myc has no persistent tertiary structure, yet regions corresponding to Myc homology boxes 1 and 2 (MBI and MBII, respectively) have molten globule-like characteristics. B-Myc binds to MM-1 in a specific manner without becoming highly structured. The local regions of B-Myc involved in binding differ for MM-1 and TBP, and regions not identified by mutagenesis are found to be involved in MM-1 binding. The results provide new insights into Myc N-terminal protein-protein interactions. We propose a model for Myc regulation through differential involvement of MBI and MBII in the binding of Myc interacting proteins.

Amino Acid Sequence↗
PubMed1997

Increased transcription of the E mu-myc transgene and mRNA stabilisation produce only a modest elevation in Myc protein.

Mice bearing the E mu-myc transgene, which links the immunoglobulin heavy chain enhancer (E mu) with c-myc, are predisposed to developing B cell lymphomas. Several B lineage cell lines have been isolated from these animals, and some have been converted to macrophages following infection with v-raf. In this study we compared the regulation of myc expression in E mu-myc B lymphoma lines, their macrophage counterparts and other non-myc transformed B cell lines. Nuclear run-on analyses demonstrated that transcription of the transgene was elevated in E mu-myc B cell lines. Moreover, the presence of a 600 bp phiX174 marker in the 3' end of the transgene produced a marked stabilisation of this RNA species. Consequently, steady state myc mRNA levels in the E mu-myc B lymphoma cells were tenfold higher than the macrophage derivatives and non-myc transformed B lineage lines. Despite the considerable difference in myc RNA levels, the E mu-myc B cell lines contained only 30-50% more Myc protein than the other cell lines. This discrepancy between RNA and protein content was not due to increased degradation of the protein as the half life was normal in the transgenic cell lines. These results indicate that both E mu and phiX174 sequences influence transgenic myc expression and that protein levels do not correlate with RNA content in E mu-myc cell lines.

Animals↗
PubMed2006

Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation.

Protein phosphatase 2A (PP2A) plays a prominent role in controlling accumulation of the proto-oncoprotein c-Myc. PP2A mediates its effects on c-Myc by dephosphorylating a conserved residue that normally stabilizes c-Myc, and in this way, PP2A enhances c-Myc ubiquitin-mediated degradation. Stringent regulation of c-Myc levels is essential for normal cell function, as c-Myc overexpression can lead to cell transformation. Conversely, PP2A has tumor suppressor activity. Uncovering relevant PP2A holoenzymes for a particular target has been limited by the fact that cellular PP2A represents a large heterogeneous population of trimeric holoenzymes, composed of a conserved catalytic subunit and a structural subunit along with a variable regulatory subunit which directs the holoenzyme to a specific target. We now report the identification of a specific PP2A regulatory subunit, B56alpha, that selectively associates with the N terminus of c-Myc. B56alpha directs intact PP2A holoenzymes to c-Myc, resulting in a dramatic reduction in c-Myc levels. Inhibition of PP2A-B56alpha holoenzymes, using small hairpin RNA to knock down B56alpha, results in c-Myc overexpression, elevated levels of c-Myc serine 62 phosphorylation, and increased c-Myc function. These results uncover a new protein involved in regulating c-Myc expression and reveal a critical interconnection between a potent oncoprotein, c-Myc, and a well-documented tumor suppressor, PP2A.

Catalytic Domain↗
PubMed2003

Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels.

c-Myc is a predominantly nuclear transcription factor that is a substrate for rapid turnover by the proteasome system. Cancer-related mutations in c-Myc lead to defects in its degradation and thereby contribute to the increase in its cellular level that is associated with the disease. Little is known about the mechanisms that target c-Myc to the proteasomes. By using a GFP fusion protein and live analysis we show that c-Myc shuttles between the nucleus and cytoplasm and thus it could be degraded in either compartment. Strikingly, at elevated levels of expression c-Myc accumulates at nucleoli in some cells, consistent with saturation of a nucleolus-associated degradation system in these cells. This idea is further supported by the observation that proteasome inhibitor treatment causes accumulation of c-Myc at the nucleoli of essentially all cells. Under these conditions c-Myc is relatively stably associated with the nucleolus, as would be expected if the nucleolus functions as a sequestration/degradation site for excess c-Myc. Furthermore, during elevated c-Myc expression or proteasome inhibition, nucleoli that are associated with c-Myc also accumulate proteasomes. c-Myc and proteasomes co-localise in intranucleolar regions distinct from the dense fibrillar component of the nucleolus. Based on these results we propose a model for c-Myc downregulation where c-Myc is sequestered at the nucleoli. Sequestration of c-Myc is accompanied by recruitment of proteasomes and may lead to subsequent degradation.

Active Transport, Cell Nucleus↗
PubMed1991

myc, max, and a novel rlf-L-myc fusion protein in small-cell lung cancer.

The functional properties of Myc proteins are likely to be modulated by interactions with other nuclear proteins. One such protein called Max has already been characterized (1). Through their homologous helix-loop-helix and leucine zipper structures, Myc and Max proteins form heterodimers that bind to specific DNA sequences more efficiently than Myc or Max alone. We have recently identified delta Max, a naturally occurring truncated version of Max, which is also able to dimerize with Myc in the nucleus, but is cytoplasmic in the absence of Myc. These two forms of Max can act either as enhancers or suppressors of cotransformation by c-myc and ras. Oncogenic activation of myc genes in human cancer involves deregulated myc expression. Oncogenes of the myc family are activated in several types of human tumors as a result of gene amplification or chromosomal translocation. We have recently characterized a gene fusion and a chimeric protein product formed by L-myc and part of a novel gene called rlf in small-cell lung cancer (SCLC) cell lines. Although the chimeric mRNAs were shown to be identical, they result from distinct DNA rearrangements. We have also established a physical linkage between normal rlf and L-myc using pulsed field gel electrophoresis. Thus, the rlf-L-myc gene fusions are due to similar but not identical intrachromosomal rearrangements at 1p32. Similar in vivo rearrangements involving rlf and L-myc have been found in at least one primary SCLC tumor. The presence of independent genetic lesions that cause the formation of identical chimeric rlf-L-myc proteins suggests a role for the fusion protein in the development of these SCLC tumors.

Amino Acid Sequence↗
PubMed2003

Development of a real-time reverse transcription polymerase chain reaction assay for c-myc expression that allows the identification of a subset of c-myc+ diffuse large B-cell lymphoma.

Absence of a reliable method for determining the level of c-myc expression has impeded the analysis of its biological and clinical relevance in tumors. We have standardized the conditions for a real-time reverse transcription polymerase chain reaction analysis for c-myc expression, including the selection of an endogenous reference (18S rRNA), the adequate number of measurements for each sample (2 cDNA in triplicate), and suitable controls for determining inter- and intrarun variability (standard curve and calibrator). Subsequently, in a series of 56 non-Hodgkin's lymphomas, we analyzed the expression of c-myc mRNA, using real-time reverse transcription polymerase chain reaction, and of other functionally related proteins (bcl-6, p27, cyclin D3, and p53). As expected, all eight Burkitt's lymphoma cases analyzed had high levels of c-myc mRNA expression compared with that observed in reactive lymphoid tissue. There was a wider range of expression in diffuse large B-cell lymphoma, with 30% (15 of 48) of cases overexpressing c-myc. This overexpression was largely independent of c-myc translocations (4 of 5), as demonstrated by fluorescence in situ hybridization. In this large B-cell lymphoma series, a high level of c-myc expression predicted lower survival probability, irrespectively of the International Prognostic Index risk group classification. A slightly increased frequency of p53 inactivation was observed in the cases with c-myc overexpression, which suggests a growth advantage in lymphomas with concurrent deregulation of c-myc and p53. In addition, a moderate increase in bcl-6 protein expression was observed in the c-myc-positive cases, suggesting the existence of a complex interrelationship between these two genes. These findings suggest that c-myc may play a relevant role in the pathogenesis of a subset of large B-cell lymphoma and suggest the existence of additional regulatory mechanisms of c-myc expression to c-myc rearrangements.

B-Lymphocytes↗
PubMed2025

A tumorigenesis threshold for endogenous Myc revealed by dosage-compensation for Myc-haploinsufficiency in the absence of p53.

The MYC proto-oncogene is crucial for neoplasia in most tumors. Overexpressed, oncogenic MYC amplifies the flux through most major processes but does not specify a unique carcinogenic pathway. This "amplifier" model suggests that MYC must exceed an expression threshold to become oncogenic. We designed a genetic test of this model, using the mouse Trp53 null mutant (p53KO) as a highly robust tumor generator to examine the effect of a modest change in the endogenous Myc level (Myc +/-). Strikingly, tumor-free survival is greatly extended in p53KO mice with haploid Myc gene-dosage, yet in the tumors that do develop (mainly hemangiosarcomas and thymic lymphomas), their Myc deficit has been invariably compensated either by increasing Myc genomic dosage (hemangiosarcomas) or expression (lymphomas). Furthermore, acutely halving the endogenous Myc gene-dosage in established tumor allografts curtails growth rates. These results indicate that even an incremental reduction of MYC activity can be salutary in cancer and that one of the major tumor suppressor functions of p53 derives from its ability to prevent MYC overexpression. Myc generates acute DNA damage by several mechanisms and accordingly, p53's anti-Myc function may be inextricably linked to its role in genome integrity surveillance.

Myc haplo-insufficiency↗
PubMed1999

Posttranslational regulation of Myc function in response to phorbol ester/interferon-gamma-induced differentiation of v-Myc-transformed U-937 monoblasts.

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.

Antineoplastic Agents↗
PubMed1994

Interaction of c-Myc with the pRb-related protein p107 results in inhibition of c-Myc-mediated transactivation.

The product of the c-myc proto-oncogene, c-Myc, is a sequence-specific DNA binding protein with an N-terminal transactivation domain and a C-terminal DNA binding domain. Several lines of evidence indicate that c-Myc activity is essential for normal cell cycle progression. Since the abundance of c-Myc during the cell cycle is constant, c-Myc's activity may be regulated at a post-translational level. We have shown previously that the N-terminus of c-Myc can form a specific complex with the product of the retinoblastoma gene, pRb, in vitro. These data suggested a model in which pRb, or pRb-related proteins, regulate c-Myc activity through direct binding. We show here that the pRb-related protein p107, but not pRb itself, forms a specific complex with the N-terminal transactivation domain of c-Myc in vivo. Binding of p107 to c-Myc causes a significant inhibition of c-Myc transactivation. Expression of c-Myc releases cells from a p107-induced growth arrest, but not from pRb-induced growth arrest. Our data suggest that p107 can control c-Myc activity through direct binding to the transactivation domain and that c-Myc is a target for p107-mediated growth suppression.

Binding Sites↗
PubMedDate not supplied

Alcohol inhibits neurite extension and increases N-myc and c-myc proteins.

Alcohol teratogenesis may be due, in part, to inhibition of neuronal differentiation by alcohol. Because decreases in the N-myc and c-myc proteins are believed to be linked causally to neuronal differentiation, we hypothesized that alcohol would increase N-myc and c-myc proteins in undifferentiated neuronal cells and would oppose the decreases in these two proteins that normally precede differentiation. In undifferentiated LA-N-5 cultured human neuroblastoma cells, alcohol increased N-myc protein levels (178% vs. control cells) and c-myc levels (222% of control). Retinoic acid decreased N-myc and c-myc and induced neurite outgrowth (a differentiation marker). Alcohol prevented retinoic acid-elicited decreases in both myc isoforms and prevented neurite outgrowth. A significant 100% increase in c-myc and an upward trend (48%) in N-myc were observed in CA1 pyramidal neurons of the dorsal hippocampus in mouse fetuses exposed prenatally to alcohol. These data suggest that increases in N-myc and c-myc protein levels are associated with inhibition of neurite extension by alcohol.

Animals↗
PubMed2000

Promotion of growth and apoptosis in c-myc nullizygous fibroblasts by other members of the myc oncoprotein family.

c-myc nullizygous fibroblasts (KO cells) were used to compare the abilities of c-myc, N-myc and L-myc oncoproteins to accelerate growth, promote apoptosis, revert morphology, and regulate the expression of previously described c-myc target genes. All three myc oncoproteins were expressed following retroviral transduction of KO cells. The proteins all enhanced the growth rate of KO cells and significantly shortened the cell cycle transition time. They also accelerated apoptosis following serum deprivation, reverted the abnormal KO cell morphology, and modulated the expression of previously described c-myc target genes. In most cases, L-myc was equivalent to c-myc and N-myc in restoring all of the c-myc-dependent activities. These findings contrast with the previously reported weak transforming and transactivating properties of L-myc. Myc oncoproteins may thus impart both highly similar as well as dissimilar signals to the cells in which they are expressed.

Animals↗
PubMed1999

The polyadenylation inhibitor cordycepin (3'dA) causes a decline in c-MYC mRNA levels without affecting c-MYC protein levels.

Study of the distribution of the poly(A) tail length of c-myc mRNA in several cell lines revealed a distinct, prevailing population with short poly(A) tails, derived through sequential deadenylation. To elucidate the possible in vivo function of this distinct short tailed c-myc mRNA population, the polyadenylation inhibitor cordycepin was used. This resulted in a decline in steady state c-myc mRNA levels with the remaining messenger mostly oligoadenylated. However, c-MYC proteins did not follow the reduction of the c-myc mRNA. On the other hand, in cells exposed to physiological agents known to downregulate c-myc expression, the reduction of mRNA steady state levels, was reflected upon c-MYC protein levels. The dissociation between c-myc mRNA and protein levels caused by cordycepin was not due to the stabilization of the c-MYC proteins and was not an indiscriminate effect since in the presence of cordycepin, c-fos mRNA and protein levels concomitantly declined. Our data indicate that under these conditions, a long poly(A) tail is not instrumental for c-myc mRNA translation and furthermore, the discrepancy in the steady state of c-myc mRNA level: c-MYC protein ratio between control cells and cells treated with cordycepin indicates that c-myc mRNA is subjected to translational control.

Deoxyadenosines↗