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 343 records · Page 19Linked to original sources
PubMed1992

Growth inhibition of N1E-115 mouse neuroblastoma cells by c-myc or N-myc antisense oligodeoxynucleotides causes limited differentiation but is not coupled to neurite formation.

Antisense oligodeoxynucleotides were found to be stable in the culture medium containing fetal calf serum (heat-inactivated 30 minutes at 65 degrees C) and in cells. Antisense oligomer treatment causes cessation of mitoses, but does not lead to morphological differentiation. Under antisense conditions, we have observed an increase in the amount of two neurospecific protein, namely peripherin and gamma-enolase. Comparison of the results obtained with chemical inducers and antisense oligodeoxynucleotides allows us to postulate three phases in N1E-115 differentiation: the first correspond to the arrest of mitosis, the second to the expression of a limited neuronal program, and the third to the morphological and electrophysiological differentiation.

Animals↗
PubMed1995

Methionine deprivation regulates the translation of functionally-distinct c-Myc proteins.

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)

Animals↗
PubMed1996

Identification of sequences in c-myc mRNA that regulate its steady-state levels.

The level of cellular myc proto-oncogene expression is rapidly regulated in response to environmental signals and influences cell proliferation and differentiation. Regulation is dependent on the fast turnover of c-myc mRNA, which enables cells to rapidly alter c-myc mRNA levels. Efforts to identify elements in myc mRNA responsible for its instability have used a variety of approaches, all of which require manipulations that perturb normal cell metabolism. These various approaches have implicated different regions of the mRNA and have led to a lack of consensus over which regions actually dictate rapid turnover and low steady-state levels of c-myc mRNA. To identify these regions by an approach that does not perturb cell metabolism acutely and that directly assesses the effect of a c-myc mRNA region on the steady-state levels of c-myc mRNA, we developed an assay using reverse transcription and PCR to compare the steady-state levels of human myc mRNAs transcribed from two similarly constructed myc genes transiently cotransfected into proliferating C2C12 myoblasts. Deletion mutations were introduced into myc genes, and the levels of their mRNAs were compared with that of a near-normal, reference myc mRNA. Deletion of most of the myc 3' untranslated region (UTR) raised myc mRNA levels, while deletion of sequences in the myc 5' UTR (most of exon 1), exon 2, or the protein-coding region of exon 3 did not, thus demonstrating that the 3' UTR is responsible for keeping myc mRNA levels low. Using a similar reverse transcription-PCR assay for comparing the steady-state levels of two beta-globin-myc fusion mRNAs, we showed that fusion of the myc 3' UTR lowers globin mRNA levels by destabilizing beta-globin mRNA. Surprisingly, fusion of the protein-coding region of myc exon 3 also lowered globin mRNA steady-state levels. Investigating the possibility that exon 3 coding sequences may play some other role in regulating c-myc mRNA turnover, we demonstrated that these sequences, but not myc 3' UTR sequences, are necessary for the normal posttranscriptional downregulation of c-myc mRNA during myoblast differentiation. We conclude that, while two elements within c-myc mRNA can act as instability determinants in a heterologous context, only the instability element in the 3' UTR regulates its steady-state levels in proliferating C2C12 cells.

Animals↗
PubMed1998

A c-myc antisense oligonucleotide inhibits human retinal pigment epithelial cell proliferation.

The purpose of this work was to investigate if MYC-dependent intracellular mitogenic pathway is active in cultures of human retinal pigment epithelial (hRPE) cells and whether myc antisense phosphorotioate oligonucleotides (c-myc-AS-ODN) are useful tools for inhibiting the proliferation of hRPE cells. Cultures of hRPE cells were established from adult human corneal donors. These cells were positively stained for cytokeratins and vimentin. Myc mRNA expression was determined by Northern blot analysis and it was determined by means of immunofluorescence if MYC was expressed. C-myc-AS-ODN effect on cell proliferation was estimated by evaluating the incorporation of 5-bromo-2'-deoxy-uridine into cellular DNA. Cell number was estimated by using a tetrazolium bromide based colorimetric method. Human RPE cells in culture expressed MYC and myc mRNA as well as prothymosin alpha mRNA--a gene whose transcription is under MYC control--indicating that MYC-dependent intracellular mitogenic pathway is active in these cells. In accordance with this, we found that blocking the expression of myc by the addition of c-myc-AS-ODN to the culture medium inhibited hRPE cell proliferation. The effect of the c-myc-AS-ODN was found to be sequence specific (the use of a control oligonucleotide with the same sequence but in an opposite direction had no effect) and dose-dependent (4 microM was the lowest effective dose tested). By using RT-PCR we found that the c-myc-AS-ODN inhibition of cell proliferation was related to a diminution in c-myc mRNA expression, and by immunofluorescence we detected a diminution in c-MYC protein staining in RPE cells after 48 hr of treatment with c-myc-AS-ODN. Furthermore, growth inhibition remained for at least 5 days after addition of a single dose of the c-myc-AS-ODN to the culture. We conclude that hRPE cell proliferation is under MYC control. Blocking the expression of myc by c-myc-AS-ODN inhibited hRPE cell proliferation. These findings establish a rationale for investigating the potential use of a c-myc-AS-ODN as a novel therapeutical tool in the treatment of Proliferative Vitreoretinopathy.

Adult↗
PubMed1990

myc gene amplification and expression in primary human neuroblastoma.

Although N-myc amplification in neuroblastomas correlates with poor prognosis, not all neuroblastomas which fail to respond to therapy have N-myc amplification. To determine whether other modes of myc gene activation underlie progression of some neuroblastomas, 45 were analyzed for amplification of N-myc, c-myc and L-myc and 26 were studied for transcription of these oncogenes. N-myc amplification was found in 6 of 45 tumors; no tumor had amplification of c-myc or L-myc. Transcription of both N-myc and c-myc occurred in 21 of 26 neuroblastomas. No tumor without N-myc amplification had a level of N-myc expression near that of a tumor or cell line with amplification. One tumor with N-myc amplification was the only specimen with N-myc but not c-myc expression. Five samples had c-myc but not N-myc expression; all had histological features of ganglioneuroma. DNA index did not correlate with myc gene amplification or expression. It is concluded that N-myc and c-myc are commonly expressed in primary untreated neuroblastomas, but in the absence of N-myc amplification, expression of these genes does not appear to correlate with disease progression.

Adolescent↗
PubMed1997

Autoregulation of the human N-myc oncogene is disrupted in amplified but not single-copy neuroblastoma cell lines.

Amplification of the N-myc gene is a significant adverse prognostic factor in neuroblastoma, a common childhood tumor. In non-transformed cells, myc expression is controlled through an autoregulatory circuit, through which elevated Myc protein levels lead to down-regulation of myc transcription. The precise mechanism of myc gene autoregulation is unknown. Loss of c-myc autoregulation has been documented in transformed cells from a number of different lineages, but N-myc autoregulation has not yet been investigated. In neuroblastoma, the increased N-Myc protein produced by amplified tumors would be expected to silence N-myc transcription if the autoregulatory loop were intact. To determine whether N-myc autoregulation is operative in human neuroblastoma, and to localize cis-acting elements which mediate N-myc autosuppression, we transfected a series of N-myc 5' promoter constructs into a panel of human neuroblastoma cell lines carrying one or multiple copies of N-myc. The transfected promoter was equally active in single-copy and amplified lines. Significant promoter activity in the presence of abundant Myc protein in amplified neuroblastoma lines indicates that autoregulation is disabled in this subset of tumors. To investigate whether single-copy lines produce insufficient N-Myc protein to trigger autosuppression yet retain an intact autoregulatory circuit, we transfected neuroblastoma lines with 5' promoter constructs in the presence of a c- or N-myc expression vector. Overexpression of c- or N-Myc resulted in diminution of activity of both the transfected promoter and the endogenous N-myc gene in single-copy, but not amplified lines. Using a series of 5' promoter-deletion minigenes, we localized a cis-acting element required for autoregulation close to the transcription start sites. While the precise mechanism of autosuppression remains unknown, we demonstrated that Myc is incapable of silencing the adenovirus major late promoter (AdMLP) in neuroblastoma cells, indicating that Myc suppression of its own promoter and the AdMLP involve distinct components. These studies provide the first systematic investigation of autoregulation in neuroblastoma, and indicate that single-copy neuroblastoma lines produce insufficient N-Myc protein to activate downstream effector(s) of autosuppression; the autoregulatory circuit is otherwise intact. Amplified lines, in contrast, have lost autoregulation.

Adenoviridae↗