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PubMed2004

Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation.

Recent studies of oncogene dependence in conditional transgenic mice have suggested the exciting possibility that transient or prolonged MYC inactivation may be sufficient for sustained reversal of the tumorigenic process. In contrast, we report here that following oncogene downregulation, the majority of c-MYC-induced mammary adenocarcinomas grow in the absence of MYC overexpression. In addition, residual neoplastic cells persist from virtually all tumors that do regress to a nonpalpable state and these residual cells rapidly recover their malignant properties following MYC reactivation or spontaneously recur in a MYC-independent manner. Thus, MYC-induced mammary tumor cells subjected to either brief or prolonged MYC inactivation remain exquisitely sensitive to its oncogenic effects and characteristically progress to a state in which growth is MYC-independent.

Adenocarcinoma↗

PubMed2003

Cell transformation by the v-myc oncogene abrogates c-Myc/Max-mediated suppression of a C/EBP beta-dependent lipocalin gene.

Using differential hybridization techniques, a cDNA clone (Q83) was isolated that corresponds to a highly abundant mRNA in quail embryo fibroblasts transformed by the v-myc oncogene. The deduced 178 amino acid protein product of Q83 contains an N-terminal signal sequence and a lipocalin sequence motif, the hallmark of a family of secretory proteins binding and transporting small hydrophobic molecules of diverse biological function, including retinoids and steroids. The quail Q83 protein displays 87% sequence identity with a developmentally regulated chicken protein, termed p20K or Ch21. Cell transformation specifically by v-myc, but not by other oncogenic agents, induces high-level expression of Q83 mRNA and of the Q83 protein. Nucleotide sequence analysis and transcriptional mapping revealed that the Q83 gene encompasses seven exons with the coding region confined to exons 1 through 6. The promoter region contains consensus binding sites for the transcriptional regulators Myc and C/EBP beta. Transcriptional activation of Q83 is principally dependent on C/EBP beta, but is blocked in normal cells by the endogenous c-Myc/Max/Mad transcription factor network. In v-myc-transformed cells, high-level expression of the v-Myc protein and formation of highly stable v-Myc/Max heterodimers leads to abrogation of Q83 gene suppression and activation by C/EBP beta. A 157 amino acid residue recombinant protein representing the secreted form of Q83 was used for structure determination by nuclear magnetic resonance spectroscopy. Q83 folds into a single globular domain of the lipocalin-type. The central part consists of an eight-stranded up-and-down beta-barrel core flanked by an N-terminal 3(10)-like helix and a C-terminal alpha-helix. The orientation of the C-terminal alpha-helix is partially determined by a disulfide bridge between Cys59 and Cys152. The three-dimensional structure determination of the Q83 protein will facilitate the identification of its authentic ligand and the assessment of its biological function, including the putative role in myc-induced cell transformation.

Amino Acid Sequence↗

PubMed1997

Overexpression of c-Myc and cell immortalization alters c-Myc phosphorylation.

Using an extensive series of deletion and site-specific mutation constructs, we have identified five new phosphorylation sites in c-Myc in the N-terminal transactivation domain and near the C-terminal DNA binding/heterodimerization domain. We have also found that Thr-58 phosphorylation is regulated by specific cellular events. When c-Myc is overexpressed in cells Thr-58 phosphorylation was greatly enhanced in the overexpressed, exogenous c-Myc as compared with the endogenous protein. In contrast, an inhibition of Thr-58 phosphorylation and an enhancement of Serine 62 phosphorylation was observed in c-Myc from immortalized cells compared with primary cells. No significant changes in c-Myc phosphorylation were found when transformed and nontransformed cells were compared. Finally, mutations at these phosphorylation sites, either individually or in combination with previously described sites, did not affect the ability of c-Myc to transactivate through the CACGTG Myc/Max DNA binding sites. These results further suggest that either the molecular role for c-Myc phosphorylation does not involve modulating transcriptional activity of c-Myc or that the CACGTG site does not represent a physiological promoter element.

3T3 Cells↗

PubMed2000

Ras/MEK signaling suppresses Myc-dependent apoptosis in cells transformed by c-myc and activated ras.

Cooperation of myc and activated ras has been suggested to cause malignant cell transformation but the mechanism is still unknown. Here we isolated a transformed cell line in which activation of c-Myc and Ras are independently controllable, and show that after establishment of the transformed state by c-myc and activated ras, removal of activated Ras initiates apoptosis that is dependent on c-Myc activity. Apoptosis is also initiated by an inhibitor of MEK (MAPK/ERK kinase), a kinase downstream of Ras, and apoptosis is blocked by activated Mek1. These results suggest that one of the conditions required for establishment of the transformed state is a block of apoptosis involving MEK activity. We tested the effect of MEK inhibition on cells transformed by various oncogenes. Suppression of apoptosis by MEK is not critical in general, but in cells transformed by c-myc plus a gene that activates the MAPK cascade it is necessary to avoid cell death. Activated Ras/MEK did not suppress c-myc-dependent apoptosis due to serum-limitation. Overexpression of chicken bcl-xL suppressed apoptosis under serum-limiting conditions, but not apoptosis initiated by Ras/MEK inhibition in cells transformed by myc and activated ras. Altogether, these results suggest the existence of a novel regulatory mechanism for myc-dependent apoptosis in certain transformed cells.

Animals↗

PubMed2002

The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2.

Gain of chromosome 17q material is the most frequent genetic abnormality in neuroblastomas. The common region of gain is at least 375 cR large, which has precluded the identification of genes with a role in neuroblastoma pathogenesis. Neuroblastoma also frequently show amplification of the N-myc oncogene, which correlates closely with 17q gain. Both events are strong predictors of unfavorable prognosis. To identify genes that are part of the N-myc downstream pathway, we constructed SAGE libraries of an N-myc transfected and a control cell line. This identified the chromosome 17q genes nm23-H1 and nm23-H2 as being 6-10 times induced in the N-myc expressing cells. Northern and Western blot analysis confirmed this up-regulation. Time-course experiment shows that both genes are induced within 4 h after N-myc is switched on. Furthermore, we demonstrate also that c-myc can up-regulate nm23-H1 and nm23-H2 expression. Neuroblastoma tumor and cell line panels reveal a striking correlation between N-myc amplification and mRNA and protein expression of both nm23 genes. We show that the nm23 genes are located at the edge of the common region of chromosome 17q gain previously described in neuroblastoma cell lines. Our findings suggest that nm23-H1 and nm23-H2 expression is increased by 17q gain in neuroblastoma and can be further up-regulated by myc overexpression. These observations suggest a major role for nm23-H1 and nm23-H2 in tumorigenesis of unfavorable neuroblastomas.

Chromosomes, Human, Pair 17↗

PubMed1991

Developmentally regulated alternative splicing in the Xenopus laevis c-Myc gene creates an intron-1 containing c-Myc RNA present only in post-midblastula embryos.

Two distinct c-Myc RNA classes have been identified in Xenopus laevis, presumably expressed from the duplicated c-Myc locus (1, 6). The major Xenopus c-Myc transcripts arise from sites termed P1 and P2 similarly to those of the mammalian c-Myc genes. I have used a cloned Xenopus c-Myc gene to examine the regulated pattern of expression from this gene during early Xenopus embryogenesis. Analysis of the pattern of transcript processing indicates that not only are P1 and P2 differentially active during early development but alternatively spliced c-Myc RNAs are generated which contain sequences of the first intron. These intron-1 containing c-Myc RNAs are generated by alternative splicing of transcripts initiated from the major transcription start site, P2, and are observed only in RNA samples from post-midblastula embryos or Xenopus tissue culture cells. Xenopus tissue culture cells synthesize two major c-Myc proteins (p61 and p64). Xenopus RNAs that do not contain intron-1 sequences synthesize only the p61 species. Two closely spaced ATG codons at the 5' end of exon-2 are utilized equivalently to generate a p61 doublet. Intron-1 containing RNAs utilize an ATG codon in the intron sequences to synthesize the p64 species as well as the exon-2 ATG codons to synthesize the p61 doublet.

Animals↗

PubMed1989

Contrasting patterns of myc and N-myc expression during gastrulation of the mouse embryo.

myc and N-myc are related genes whose similar protein products may be used for different purposes in vertebrate organisms. We have explored this possibility by using hybridization in situ to examine the expression of myc and N-myc during gastrulation of mouse embryos. Throughout gastrulation, myc RNA was most abundant in extraembryonic cells; by contrast, N-myc RNA was found at highest levels in the expanding primitive streak and other portions of the embryonic mesoderm. Differentiation of mesoderm to epithelioid cells was accompanied by diminished expression of N-myc. Expression of myc was not an inevitable correlate of cellular proliferation. Instead, the gene appeared to be regulated in concert with changes that affect a diversity of cellular properties, including proliferation, invasiveness, and differentiation.

Animals↗

PubMed1989

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↗

PubMed2003

Upregulation of the oncogene c-myc in Barrett's adenocarcinoma: induction of c-myc by acidified bile acid in vitro.

BACKGROUND AND AIMS: C-myc over expression is implicated in malignancy although to date this has not been studied in Barrett's metaplasia. We sought to determine c-myc expression in the malignant progression of Barrett's metaplasia and whether it may be induced by bile acids seen in gastro-oesophageal refluxate. METHODS: C-myc protein and mRNA levels were assessed in 20 Barrett's metaplasia and 20 oesophageal adenocarcinoma samples by western blotting and real time polymerase chain reaction. Levels of c-myc and proliferation were also assessed in cell lines OE21, OE33, SW-480, and TE-7 stimulated with pulses or continuous exposure to the bile acids deoxycholic acid and chenodeoxycholic acid. RESULTS: C-myc protein was upregulated in 50% of Barrett's metaplasia and 90% of oesophageal adenocarcinoma samples compared with squamous, gastric, and duodenal controls. C-myc immunolocalisation in Barrett's metaplasia revealed discrete nuclear localisation, becoming more diffuse with progression from low to high grade dysplasia to adenocarcinoma. Both continual and pulsed bile acid induced c-myc at pH 4, with no effect at pH 7 or with acidified media alone. Pulsed bile acid treatment induced proliferation (p<0.05); in contrast, continuous exposure led to suppression of proliferation (p<0.05). CONCLUSIONS: We have shown upregulation of c-myc with malignant progression of Barrett's metaplasia and suggest that acidified bile may be a novel agent responsible for induction of this oncogene.

Adenocarcinoma↗

PubMed2006

Regulation of Myc function by ARF: checkpoint for Myc-induced oncogenesis.

The alterative reading frame (ARF) protein is unique in its capacity to interact with Mdm2 thus facilitating p53-dependent cell cycle arrest and apoptosis. ARF also acts in a p53-independent manner in which it binds to Myc and interferes with transcriptional activation by Myc thereby inhibiting Myc-induced cell proliferation and transformation. Interestingly, ARF does not interfere with apoptosis induction by Myc. ARF-Myc interaction studies have been performed with mouse p19(ARF). Human p14(ARF) provides functions similar to p19(ARF). However, p14(ARF) has limited sequence homology with p19(ARF) and these proteins show subtle functional differences, especially in the contexts of immortalization and senescence. The studies by Amente et al. confirm that interaction of p14(ARF) with Myc also interferes with the transcriptional activity of Myc thus establishing the general role of ARF as a checkpoint for Myc-induced oncogenesis.

Cell Line↗

PubMed2000

c-Myc antisense limits rat liver regeneration and indicates role for c-Myc in regulating cytochrome P-450 3A activity.

Expression of c-myc protein is associated with cell proliferation. The present study uses antisense oligomers to inhibit c-myc expression in the regenerating rat liver after 70% partial hepatectomy (PH). Antisense phosphorodiamidate morpholino oligomers (novel DNA analogs) were administered i.p. immediately after surgery to block expression of c-myc within the first 24 h after PH. A 20-mer PMO complimentary to the c-myc mRNA at the translation start site was an effective sequence (AVI-4126, 5'-ACGTTGAGGGGCATCGTCGC-3'). A single i.p. dose of 0.5 mg/kg AVI-4126 caused reduction of the regenerating liver c-myc protein in a sequence-specific and dose-dependent manner. Inhibition of c-myc expression resulted in reduction of proliferating cell nuclear antigen and arrested cells in the G(0)/G(1) phase of the cell cycle. The ratio of G(2):G(0) cell populations in the regenerating liver 24 h after PH dropped from 29.1 in saline vehicle-treated rats to 18.0 in rats treated with 2.5 mg/kg AVI-4126. The expression of cell cycle checkpoint protein p53 was inhibited with increasing doses of AVI-4126, but expression of p21(waf-1) was unaffected. The activity of cytochrome P-450 3A2 (CYP3A2) was evaluated by immunoblot analysis and erythromycin N-demethylation. AVI-4126 did not alter CYP3A activity in nonhepatectamized animals but showed a dose-dependent decrease in PH rats. We conclude that AVI-4126, antisense oligomer to c-myc, can reduce cell proliferation in the regenerating rat liver. Furthermore, inhibition of c-myc may indirectly influence the expression of CYP3A.

Animals↗

PubMed2002

Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis.

The Myc basic helix-loop-helix zipper domain determines dimerization with Max and binding to the DNA E-box, both of which play a critical role in Myc regulation of growth, proliferation, tumorigenesis, and apoptosis. The mutant basic helix-loop-helix zipper domain, Omomyc, dimerizes with Myc, sequestering it in complexes unable to bind the E-box, and so acting as a potential dominant negative. Consistent with this, Omomyc reverses Myc-induced cytoskeletal disorganization in C2C12 myoblasts. Surprisingly, however, Omomyc strongly potentiates Myc-induced apoptosis in a manner dependent on Myc expression level. Expression analysis of known Myc target genes indicates that Omomyc inhibits transcriptional activation but enhances repression. These findings suggest that Omomyc can selectively trigger apoptosis in cells overexpressing Myc, possibly through the transcriptional repression of specific genes.

Animals↗

PubMed2001

[Expression of C-myc and N-myc protein in adulthood and childhood medulloblastomas and prognostic analysis].

OBJECTIVE: To detect the expression of C-myc and N-myc in medulloblastomas, the difference between adults and children, and the relation between expression and prognosis. METHODS: ABC immunostaining was used to detect C-myc and N-myc protein expression in 21 cases of adulthood medulloblastomas and 14 childhood cases. Follow-up materials were obtained to perform survival curve analysis. RESULTS: Of these 35 cases, 5 (4 children, 1 adult) showed C-myc positive expression. No N-myc expression was found. There was no relationship between expression and survival. CONCLUSION: C-myc may play a role in the tumorgenesis of medulloblastoma, especially in children, but it is of no prognostic significance. N-myc antigen may be lost during the fixation of specimens.

Adolescent↗

PubMed1990

[Relationship between human papillomavirus and oncogenes (c-myc, N-myc) amplification in human cervical cancers].

The human papillomavirus detection and oncogenes amplifications were studied on DNAs from fifteen cervical cancers. We detected HPV16 and HPV18 using Southern blot hybridization and polymerase chain reaction (PCR) technique. The positive subjects of HPVs were eight cases (53%) observed by Southern blot hybridization and fourteen cases (93%) by PCR technique. The gene amplifications of oncogenes (c-myc and N-myc) were analysed by slot-blot method and were observed in c-myc but not in N-myc. The "LARGE" gene amplification (more than five fold) in c-myc was observed in one case (7%) and the "SMALL" gene amplifications (less than five fold) were observed in six cases (40%) in human cervical cancers. Although one of five cases (20%) with HPV16 was present c-myc gene amplification, all of three cases (100%) with HPV18 were found c-myc gene amplifications. In two out of three cases obtained more than three fold c-myc gene amplifications, HPV were not detectable. It is suggested that the negative correlation between gene amplification and numbers of HPV copies exist in advanced cervical cancers.

Adult↗

PubMed1990

Antisense inhibition of single copy N-myc expression results in decreased cell growth without reduction of c-myc protein in a neuroepithelioma cell line.

The N-myc gene is transiently expressed during normal embryonic development and abnormally expressed in several tumors of neuroendocrine origin. Little is known of the function of the N-myc gene product in either normal or neoplastic tissue. We utilized synthetic antisense oligodeoxynucleotides to specifically inhibit N-myc gene expression in the neuroepithelioma cell line CHP100. These cells contain single copy N-myc alleles but overexpress c-myc. N-myc antisense oligomer treatment was found to be growth inhibitory without affecting levels of c-myc protein. N-myc antisense oligomer-treated cells also lost the characteristic cellular heterogeneity displayed by CHP100 in vitro.

Cell Division↗

PubMed2025

Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers.

The MYC oncogene is causally involved in the pathogenesis of most human cancers. The mTORC1 complex regulates MYC translation through 4EBP1 and S6K. However, agents that selectively target mTORC1 (without affecting mTORC2) have so far failed to reactivate 4EBP1 and, thus, cannot effectively suppress MYC in vivo. In contrast, nonselective inhibitors that block both mTOR complexes can activate 4EBP1, but often lack tolerability and induce immunosuppression. Here, we introduce bi-steric mTORC1-selective inhibitors, including the clinical candidate RMC-5552, which potently reactivate 4EBP1 and decrease MYC protein expression levels. Consequently, suppression of MYC signaling occurs, resulting in tumor growth inhibition through both direct effects on tumor cells and immune activation. RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic MYC amplifications and reduces MYC protein levels in vivo. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression.

Mechanistic Target of Rapamycin Complex 1↗

PubMed1985

Chromosome translocations clustered 5' of the murine c-myc gene qualitatively affect promoter usage: implications for the site of normal c-myc regulation.

Five novel murine plasma cell (PC) tumors with chromosome translocations 350-500 bp 5' of the first c-myc exon are described. The t(12;15)s of TEPC 1194, ABPC 33 and TEPC 1165 position the intact c-myc locus 5' of the Cu, C gamma 2a and C alpha IgCH genes respectively. In ABPC 17, the IgH enhancer element and adjacent switch (Su) sequences were found 5' of the first c-myc exon while this enhancer is associated with the reciprocal products of the TEPC 1194, ABPC 33 and TEPC 1033 translocations. Quantitative S1 nuclease analyses demonstrate that the ratios of transcription from the two c-myc promoters (P1 and P2) are increased 4-to 7-fold in these five tumors. With the exception of TEPC 1165, (which contains a small deletion in exon 1), such increases in P1:P2 ratios appear to be manifested by a reduction in P2 usage in comparison to other tumors without such promoter shifts. A survey of 27 additional PC and non-PC B lymphoid tumors and cell lines revealed that myc promoter shifts of this magnitude are unique to PC tumors with 5'-proximal translocations. We propose that (i) these clustered breakpoints identify a normal c-myc regulatory element located at least 350 bp 5' of c-myc exon 1; (ii) the loss or disruption of this cis-acting upstream element and the linkage of c-myc to the IgCH locus would result in abnormal expression of this oncogene in these as well as most other PC tumors.

Animals↗

PubMed1983

Expression of c-myc RNA in bursal lymphoma cell lines: identification of c-myc-encoded proteins by hybrid-selected translation.

We examined expression of the c-myc locus in four cell lines established from bursal lymphomas induced by avian leukosis virus. In all four lines the level of myc-related RNA was elevated. In three lines a majority of the myc-containing RNAs lacked viral-LTR-related sequences, in contrast to results obtained with primary tumors. This suggests that LTR sequences are not required for maintenance of high level c-myc expression. One line, RP9, has a complex pattern of myc RNAs containing LTR sequences, and one of these RNAs is packaged into virions. Using hybrid selection of RNAs with myc DNA, followed by in vitro translation, we detected translation of myc-related proteins from RNA of all four cell lines. The sizes of these proteins differ among the cell lines. The major polypeptides detected were 64, 57, and 54 kilodaltons. Events leading to elevation of c-myc transcription may be accompanied by alterations in mRNA initiation or processing that generate different protein products.

Animals↗