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PubMed1995

Quantifying c-myc expression in c-myc antisense phosphorothioate oligodeoxynucleotide-treated leukemic and colon cancer cell lines.

Antisense oligodeoxynucleotides (oligo) have been used to inhibit oncogene expression and have potential therapeutic applications. Using a 15-mer antisense phosphorothioate oligo (S-oligo), inhibition of c-myc oncogene expression and cellular proliferation is studied in two cell lines with c-myc overexpression: a colon cancer cell line (Colo 320 DM) and a promyelocytic leukemic cell line(HL-60). Quantitative analysis of c-myc mRNA transcript is performed by competitive reverse transcription-polymerase chain reaction (RT-PCR). This utilizes an RNA competitive reference standard (CRS RNA) template that is identical to the native c-myc mRNA except for a short segment deletion to allow for differentiation of the two by gel electrophoresis. A fixed quantity of test mRNA and a series of known concentrations of CRS RNA template placed in the same test tubes under identical conditions are reverse transcribed and amplified by PCR. Since the reaction is competitive, the ratio of the PCR products reflects the ratio of the initial concentrations of the two templates. After gel electrophoresis, the two PCR products are quantified densitometrically. Treating Colo 320 DM and HL-60 cells with c-myc antisense oligo and S-oligo results in a 20- to 100-fold decrease in c-myc mRNA transcripts, respectively. This inhibition is dose dependent and sequence specific (c-myc sense and missense oligo have no effects). The quantitative decrease in c-myc mRNA is associated with corresponding inhibition of c-myc oncoprotein synthesis as demonstrated by flow cytometry and Western blots. Furthermore, there is inhibition of cellular proliferation of the respective cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1989

Transrepression of the N-myc expression by c-myc protein.

In the human neuroblastoma cell line IMR32 the N-myc gene happens to be amplified and actively expressed, whereas no stable c-myc RNA can be detected in the same cells. In this report, we show that in IMR32 cells the expression of the N-myc gene is repressed by introduction of a c-myc expression vector (c-myc cDNA conjugated with an SR promoter). Moreover, dose response experiments showed that the amount of endogenous c-myc protein present in HeLa cells (which express c-myc but not N-myc) is enough to repress the expression of N-myc in IMR32 cells.

Dose-Response Relationship, Drug↗
PubMed1993

Allele-specific activation of the c-myc gene in an atypical Burkitt's lymphoma carrying the t(2;8) chromosomal translocation 250 kb downstream from c-myc.

The genetic structure and regulation of the c-myc gene was comprehensively studied for the first time in Burkitt's lymphoma with t(2;8) translocation. In a Burkitt's lymphoma cell line, KOBK101, the immunoglobulin kappa-encoding gene on chromosome 2, accompanied by its enhancer, was translocated to the pvt-1 locus located about 250 kb downstream from c-myc on chromosome 8. Only the c-myc allele on the translocated chromosome carried aberrant SalI and KpnI sites in the first intron, so the two c-myc alleles and their transcripts were analyzed separately. The c-myc allele on the untranslocated chromosome conserved the normal c-myc sequence and was transcriptionally silent. In contrast, the c-myc allele on the translocated chromosome was actively transcribed at three- to fivefold higher levels, as compared with non-malignant B-cell lines. Additionally, it carried predominant multiple mutations consisting of 64 nucleotide substitutions, three short deletions, and a one-base insertion, most of which clustered in the first exon and intron. The 24-base deletion in the first intron completely overlapped the binding site of a putative negative transcriptional factor of the 138-kDa phosphoprotein, MIF. Thus, the multiple mutations and the deregulated, allele-specific expression of c-myc were associated with the chromosomal translocation in cis. Together activation by the long-distance immunoglobulin kappa enhancer, and the alleviation of negative regulation by the mutations, seemed to cause the allele-specific activation of c-myc.

Alleles↗
PubMed2005

Nucleolar localization of hepatic c-Myc: a potential mechanism for c-Myc regulation.

The c-myc proto-oncogene encodes a transcription factor that is involved in cell proliferation, growth, differentiation, and apoptosis. Previous studies on the regulation of hepatic c-myc have focused on control of its mRNA expression, which generally correlates with hepatocyte proliferation during both liver development and liver regeneration. However, Western blot analysis showed similar levels of hepatic c-Myc in fetal and adult liver. We therefore went on to examine the abundance and distribution of hepatic c-Myc. Immunofluorescence on adult rat liver cryosections showed that c-Myc was readily detectable, but that it was largely localized to the nucleolus. In contrast, proliferating fetal hepatocytes and adult hepatocytes from regenerating liver showed a diffuse nuclear pattern. Transient transfection of adult hepatocytes with full-length HA-Myc also revealed localization to the nucleolus. Western immunoblotting studies confirmed that immunoreactive c-Myc was present in nucleolar extracts isolated from adult liver. We speculate that the nucleolus may act to sequester c-Myc in quiescent hepatocytes while providing a pool of c-Myc that is readily available to reach its targets in the nucleus.

Animals↗
PubMed2000

CDC6 interacts with c-Myc to inhibit E-box-dependent transcription by abrogating c-Myc/Max complex.

The c-myc oncogene product (c-Myc) is a transcription factor that dimerizes with Max and recognizes the E-box sequence. It plays key functions in cell proliferation, differentiation and apoptosis. It is generally thought that c-Myc transactivates genes encoding proteins essential to cell-cycle progression by binding to the E-boxes that control them. The functions of c-Myc are also thought to be modulated by its associated proteins, several of which have recently been identified. In this study, we found that c-Myc directly bound in vivo and in vitro to the N-terminal region of human CDC6, a component of the pre-replication complex, and that both co-localized in cell nuclei. CDC6 bound to the C-proximal region of c-Myc, thereby competing with Max on the E-box sequence and changing c-Myc/Max heterodimer to a Max/Max homodimer. In consequence, the E-box-dependent transcription activity of c-Myc was abrogated. These results suggest that, in addition to its DNA replication activity, CDC6 also has a role as a transcriptional suppressor of c-Myc.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2001

Myc and mammary cancer: Myc is a downstream effector of the ErbB2 receptor tyrosine kinase.

The proto-oncogene c-myc encodes a transcription factor which plays a major role in the regulation of normal cellular proliferation and is aberrantly expressed in many breast tumors. In a normal cell Myc expression levels are tightly regulated being subject to many layers of control. Errantly expressed Myc collaborates with other oncogenes to promote transformation. In this review we will focus on the association between abnormal Myc expression and mammary cancer. In particular, we will discuss the role of Myc as a downstream effector of the ErbB2 receptor tyrosine kinase which is overexpressed and constitutively activate in many mammary tumors. The cooperation between Myc and ErbB2 in transformation will be discussed in relation to clinical studies on Myc in human cancer and with consideration of transgenic models of Myc-induced mammary cancer. Data from our laboratory will be presented showing that deregulated ErbB2 activity strongly stimulates cytoplasmic signaling pathways which in turn impinge on Myc at multiple levels causing its deregulated expression.

Animals↗
PubMed1991

Amino-terminal domains of c-myc and N-myc proteins mediate binding to the retinoblastoma gene product.

The proteins encoded by the myc gene family are involved in the control of cell proliferation and differentiation, and aberrant expression of myc proteins has been implicated in the genesis of a variety of neoplasms. In the carboxyl terminus, myc proteins have two domains that encode a basic domain/helix-loop-helix and a leucine zipper motif, respectively. These motifs are involved both in DNA binding and in protein dimerization. In addition, myc protein family members share several regions of highly conserved amino acids in their amino termini that are essential for transformation. We report here that an N-terminal domain present in both the c-myc and N-myc proteins mediates binding to the retinoblastoma gene product, pRb. We show that the human papilloma virus E7 protein competes with c-myc for binding to pRb, indicating that these proteins share overlapping binding sites on pRb. Furthermore, a mutant Rb protein from a human tumour cell line that carried a 35-amino-acid deletion in its C terminus failed to bind to c-myc. Our results suggest that c-myc and pRb cooperate through direct binding to control cell proliferation.

Amino Acid Sequence↗
PubMed2003

Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2.

Poor prognosis neuroblastoma (NB) tumors are marked by amplification and overexpression of N-myc. Retinoic acid (RA) decreases N-myc levels and induces cell cycle arrest in vitro and increases event-free survival in advanced stage NB patients. In this study, we investigated the mechanism(s) by which RA regulates cell cycle and how N-myc affects NB cell cycle progression. Constitutive N-myc overexpression stimulates increases in cyclin E-dependent kinase activity and decreases in p27 resulting in increased DNA synthesis. N-myc regulates p27 levels through an increase in targeting of p27 to the proteasome via cyclin E kinase-dependent phosphorylation of p27 and its ubiquitination. N-myc also stimulates an increase in proteasome activity. In RA-treated cells in which N-myc levels decline as p27 levels increase, degradation of p27 is also decreased. However, RA does not affect the activity of proteasome. The decrease in the degradation of p27 in RA-treated cells is due in part to a decrease in the N-myc stimulated phosphorylation of p27. However, RA also decreases Skp2 levels thus impairing the ability of p27 to be ubiquitinated. Thus, RA induces both N-myc-dependent and -independent mechanisms to minimize the degradation of p27 and arrest NB cell growth.

Cell Cycle↗
PubMed1998

YY1 can inhibit c-Myc function through a mechanism requiring DNA binding of YY1 but neither its transactivation domain nor direct interaction with c-Myc.

The proto-oncoprotein c-Myc and the multifunctional transcriptional regulator YY1 have been shown previously to interact directly in a manner that excludes Max from the complex (Shrivastava et al., 1993). As binding to Max is necessary for all known c-Myc activities we have analysed the influence of YY1 on c-Myc function. We demonstrate that YY1 is a potent inhibitor of c-Myc transforming activity. The region in YY1 required for inhibition corresponds to a functional DNA-binding domain and is distinct from the domains necessary for direct binding to c-Myc. Furthermore the transactivation domain of YY1 was not necessary suggesting that gene regulation by YY1, for example through DNA bending or displacement of regulators from DNA, could be the cause for the negative regulation of c-Myc. This model of indirect regulation of c-Myc by YY1 was supported by the finding that although YY1 did not bind to the c-Myc transactivation domain (TAD) in vitro it was able to inhibit transactivation by Gal4-MycTAD fusion proteins in transient transfections. As for the inhibition of transformation, an intact DNA-binding domain of YY1 was necessary and sufficient for this effect. In addition YY1 did not alter c-Myc/Max DNA binding, further supporting an indirect mode of action. Our findings point to a role of YY1 as a negative regulator of cell growth with a possible involvement in tumor suppression.

Alanine↗
PubMed1999

Deregulated expression of c-Myc in a translocation-negative plasmacytoma on extrachromosomal elements that carry IgH and myc genes.

The induced expression of c-Myc in plasmacytomas in BALB/c mice is regularly associated with nonrandom chromosomal translocations that juxtapose the c-myc gene to one of the Ig loci on chromosome 12 (IgH), 6 (IgK), or 16 (IgL). The DCPC21 plasmacytoma belongs to a small group of plasmacytomas that are unusual in that they appear to be translocation-negative. In this paper, we show the absence of any c-myc-activating chromosomal translocation for the DCPC21 by using fluorescent in situ hybridization, chromosome painting, and spectral karyotyping. We find that DCPC21 harbors c-myc and IgH genes on extrachromosomal elements (EEs) from which c-myc is transcribed, as shown by c-myc mRNA tracks and extrachromosomal gene transfer experiments. The transcriptional activity of these EEs is supported further by the presence of the transcription-associated phosphorylation of histone H3 (H3P) on the EEs. Thus, our data suggest that in this plasmacytoma, c-Myc expression is achieved by an alternative mechanism. The expression of the c-Myc oncoprotein is initiated outside the chromosomal locations of the c-myc gene, i.e., from EEs, which can be considered functional genetic units. Our data also imply that other "translocation-negative" experimental and human tumors with fusion transcripts or oncogenic activation may indeed carry translocation(s), however, in an extrachromosomal form.

Animals↗
PubMed2000

Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma.

Translocations involving c-myc and an Ig locus have been reported rarely in human multiple myeloma (MM). Using specific fluorescence in situ hybridization probes, we show complex karyotypic abnormalities of the c-myc or L-myc locus in 19 of 20 MM cell lines and approximately 50% of advanced primary MM tumors. These abnormalities include unusual and complex translocations and insertions that often juxtapose myc with an IgH or IgL locus. For two advanced primary MM tumors, some tumor cells contain a karyotypic abnormality of the c-myc locus, whereas other tumor cells do not, indicating that this karyotypic abnormality of c-myc occurs as a late event. All informative MM cell lines show monoallelic expression of c-myc. For Burkitt's lymphoma and mouse plasmacytoma tumors, balanced translocation that juxtaposes c-myc with one of the Ig loci is an early, invariant event that is mediated by B cell-specific DNA modification mechanisms. By contrast, for MM, dysregulation of c-myc apparently is caused principally by complex genomic rearrangements that occur during late stages of MM progression and do not involve B cell-specific DNA modification mechanisms.

Chromosome Aberrations↗
PubMed2002

A Myc-associated zinc finger protein-related factor binding site is required for the deregulation of c-myc expression by the immunoglobulin heavy chain gene enhancers in Burkitt's lymphoma.

The deregulation of expression of the c-myc gene in Burkitt's lymphoma results from the translocation that links one c-myc allele to one of the immunoglobulin genes. This physical linkage promotes interactions between c-myc and immunoglobulin gene regulatory elements that affect c-myc transcription initiation and elongation. We have located a region in the c-myc promoter that is required for the complete activation by the immunoglobulin heavy chain gene enhancer. This regulatory element contains a core sequence, GGGAGG, similar to the GA box recognized by the transcription factor Myc-associated zinc finger protein (MAZ). UV cross-link analysis indicated that the mass of this protein did not correspond to that of MAZ, suggesting that a protein related to but distinct from MAZ bound to this site. Mutation of this regulatory element resulted in a loss of promoter activity induced by the immunoglobulin heavy chain gene enhancer. This site was also required for the c-myc promoter shift from P2 to P1. In vivo footprinting revealed that this site was occupied on the translocated c-myc allele but not on the untranslocated allele. Taken together, these findings suggest that this regulatory element is required for the full activation of c-myc promoter activity by the immunoglobulin heavy chain gene enhancer.

Alleles↗
PubMed2007

Inhibition of a protein-protein interaction between INI1 and c-Myc by small peptidomimetic molecules inspired by Helix-1 of c-Myc: identification of a new target of potential antineoplastic interest.

c-Myc is a transcription modulator proto-oncogene. When overexpressed, it becomes an important contributor to the multi-hit process of malignant transformation. In two earlier papers in this journal (see refs. 19 , 20) we reported that retro-inverso peptidomimetic molecules inspired by the Helix-1 of c-Myc motif could be sequence-specific antiproliferative agents active in the low micromolar range. We also found that our peptides were not opening the four-alpha-helix Myc:Max bundle. Their antiproliferative activity in cancer cell lines needs the presence of side chains projecting outside of the bundle in the corresponding native H1 motif. This observation suggested interference with an external partner. In this study we investigated the INI1:Myc interaction. INI1 is a subunit of the SWI/SNF complex (component of the enhanceosome surrounding Myc:Max heterodimer). The INI1:Myc interaction was confirmed via pull down, ELISA, and fluorescence anisotropy assays. According to the length of INI1 fragments used, we calculated Kds ranging between 1.3x10(-6) and 4.8x10(-7) M. The three different techniques applied showed that the INI1:Myc interaction was also the target of our retro-inverso peptidomimetic molecules, which seem to bind specifically at INI1. A Myc binding, 21aa INI1 fragment (minimum interacting sequence), could inspire the synthesis of a new class of more selective c-Myc inhibitors.

Amino Acid Sequence↗
PubMed1999

Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF.

The bmi-1 and myc oncogenes collaborate strongly in murine lymphomagenesis, but the basis for this collaboration was not understood. We recently identified the ink4a-ARF tumor suppressor locus as a critical downstream target of the Polycomb-group transcriptional repressor Bmi-1. Others have shown that part of Myc's ability to induce apoptosis depends on induction of p19arf. Here we demonstrate that down-regulation of ink4a-ARF by Bmi-1 underlies its ability to cooperate with Myc in tumorigenesis. Heterozygosity for bmi-1 inhibits lymphomagenesis in Emu-myc mice by enhancing c-Myc-induced apoptosis. We observe increased apoptosis in bmi-1(-/-) lymphoid organs, which can be rescued by deletion of ink4a-ARF or overexpression of bcl2. Furthermore, Bmi-1 collaborates with Myc in enhancing proliferation and transformation of primary embryo fibroblasts (MEFs) in an ink4a-ARF dependent manner, by prohibiting Myc-mediated induction of p19arf and apoptosis. We observe strong collaboration between the Emu-myc transgene and heterozygosity for ink4a-ARF, which is accompanied by loss of the wild-type ink4a-ARF allele and formation of highly aggressive B-cell lymphomas. Together, these results reinforce the critical role of Bmi-1 as a dose-dependent regulator of ink4a-ARF, which on its turn acts to prevent tumorigenesis on activation of oncogenes such as c-myc.

Animals↗
PubMed1999

Regulation of c-Myc and Max in megakaryocytic and monocytic-macrophagic differentiation of K562 cells induced by protein kinase C modifiers: c-Myc is down-regulated but does not inhibit differentiation.

We have studied the regulation and role of c-Myc and Max in the differentiation pathways induced in K562 cells by 12-O-tetradecanoyl phorbol-13 acetate (TPA) and staurosporine, an activator and inhibitor, respectively, of protein kinase C (PKC). We found that staurosporine induced megakaryocytic differentiation, as revealed by the cellular ultrastructure, platelet formation, and DNA endoreduplication. In contrast, TPA induced a differentiated phenotype that more closely resembled that of the monocyte-macrophage lineage. c-myc expression was down-regulated in K562 differentiated by both TPA and staurosporine, whereas max expression did not change in either case. Although PKC enzymatic activity was low in cells terminally differentiated with TPA and staurosporine, inhibition of PKC activity by itself did not induce c-myc down-regulation. We conclude that the c-myc gene is switched off as a consequence of the differentiation process triggered by these drugs in a manner independent from PKC. Ectopic overexpression of c-Myc in K562 cells did not affect the monocytic-macrophagic and megakaryocytic differentiation, indicating that c-Myc suppression is not required for these processes in K562. Similarly, both differentiation pathways were not affected by Max overexpression or by concomitant overexpression of c-Myc and Max. This result is in contrast with the inhibition of erythroid differentiation of K562 exerted by c-Myc, suggesting divergent roles for c-Myc/Max, depending on the differentiation pathway.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed1989

Mouse fibroblasts transformed with the human c-myc gene express a high level of mRNA but a low level of c-myc protein and are non-tumorigenic in nude mice.

Overexpression of a transfected c-myc gene under the control of a strong promoter causes the phenotypic changes of malignant transformation. We have investigated the effect of exogenous c-myc gene expression in NIH3T3 cells transfected with an intact human c-myc gene which is expressed under the control of its own promoter. The presence of the exogenous c-myc gene in the transfected cells was documented by Southern blot analysis. The transfected clones contained 20-40 copies of the human c-myc gene and demonstrated a proportional elevation in the level of c-myc mRNA which had a normal half life of 20-30 min. Despite the high level of c-myc mRNA, the transfected cells contained a relatively low level of c-myc protein and expression appears to be regulated at a post-transcriptional level. The transfected cells exhibited a decreased serum requirement for growth and formed colonies in soft agar, but were non-tumorigenic in Balb/c athymic nude mice. The morphologic evidence of transformation in the absence of tumorigenesis suggests that transfection of murine fibroblasts with multiple copies of the c-myc gene expressed under the control of its own promoter may cause partial transformation.

Animals↗
PubMed1989

Tissue-specific post-transcriptional regulation of c-myc expression in normal and H-2K/human c-myc transgenic mice.

We show that the steady-state levels of c-myc mRNAs vary considerably in different organs of normal adult mice, maximal expression being observed in lymphoid organs and minimal expression in liver and brain. Nuclear run-on analysis of c-myc gene transcription in adult liver and spleen reveals that the difference in c-myc gene expression in these two organs is due to differential post-transcriptional control. Moreover, these nuclear run-on assays indicate that no premature termination of c-myc gene transcription takes place in the nuclei of the three adult tissues analysed. In fetal liver development, we observe a decrease in c-myc mRNA, but this is not due to changes in transcriptional activity implicating post-transcriptional regulatory mechanisms. Our studies of c-myc gene expression in organs of H-2K/myc transgenic mice, harboring an H-2K promoter driven human c-myc gene, confirm that the in vivo c-myc regulation is mainly post-transcriptional and shows that sequences shared by the murine and human c-myc proto-oncogenes are involved in this control.

Animals↗
PubMed1993

[Correlation between DNA content and amplification of oncogenes (c-myc, L-myc, c-erbB-2) and correlation with prognosis in 143 cases of resected lung cancer].

DNA content analysis using flow cytometry and amplification of c-myc, L-myc, and c-erbB-2 oncogenes in 143 cases of resected lung cancer were analyzed using the same specimen, and we examined the correlation with prognosis of DNA content and amplification of oncogenes. There were 54 DNA diploid cases (38%), 81 DNA aneuploid cases (57%) and 8 DNA multiploid cases. Analysis of oncogene amplification revealed 22 cases of c-myc, 4 cases of L-myc, and 22 cases of c-erbB-2. In curatively resected cases, the 5-year survival rate was 65% in 31 DNA diploid cases, and 36% in 40 DNA aneuploid cases. There was a statistically significant difference between the two groups (p < 0.02). However, in non-curatively resected cases, the 5-year survival rate was 11% in 23 DNA diploid cases, and 33% in 49 DNA aneuploid cases. There were no statistically significant differences among these groups. The correlation between DNA content and amplification of oncogenes was as follows. In DNA diploid cases, there were 4 cases of c-myc, and 6 cases of c-erbB-2. In DNA aneuploid cases, there were 15 cases of c-myc, 4 cases of L-myc, and 15 cases of c-erbB-2. In DNA multiploid cases, there were 3 cases of c-myc, and 1 cases of c-erbB-2. Amplification of oncogenes was seen more frequently in DNA aneuploid and multiploid cases than in DNA diploid cases. In 71 curative resected cases, the 5-year survival rate for amplified cases of c-myc (10 cases) was 0%, and that of cases with no amplification was 61% (no statistically significant difference). The 5-year survival rate for amplified cases of c-erbB-2 (10 cases) was 40%, against 52% for cases with no amplification. DNA content analysis using flow cytometry was more convenient than analysis of amplification of oncogenes, and reflects the prognosis of resected lung cancer better than oncogenes. There was no relation between DNA content and gene amplification.

DNA, Neoplasm↗