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PubMed1989

Isolation and characterization of s-myc, a member of the rat myc gene family.

A 9-kilobase-pair clone containing a myc-related gene that we have designated s-myc was isolated from a rat genomic library. The entire nucleotide sequence of the cloned DNA was determined, showing that the s-myc gene contains an open reading frame consisting of 1287 base pairs without introns. In vitro transcription-translation analysis of s-myc indicated that this gene produces a protein of approximately 50 kDa. The amino acid sequence predicted from the DNA sequence showed that the s-Myc protein is closely related to the murine N-Myc protein but lacks an acidic amino acid-rich sequence commonly present in the Myc-family proteins. Studies on transfection of s-myc into rat RT4-AC tumor cells revealed that the gene produces a polyadenylylated transcript of approximately 4.7 kilobases and that its high-level expression suppresses the tumor-igenicity of RT4-AC tumor cells in nude mice.

Amino Acid Sequence↗
PubMed1992

Nuclear colocalization of c-myc protein and hsp70 in cells transfected with human wild-type and mutant c-myc genes.

Using immunofluorescence and electron microscopy we have studied the localization of wild-type and mutant c-myc proteins transiently expressed in CV-1 cells. In agreement with our previous observations, wild-type c-myc protein accumulated in large amorphous globules in the nucleus. All mutant proteins tested accumulated in the nucleus as well, but gave rise to morphologically different inclusion bodies. Many small globules appeared in cells transfected with D145-262 (deletion of amino acids 145-262), while cells transfected with D371-412 or D414-433 generated structures looking like a fine network or like beads on a string. In addition, a particulate cytoplasmic staining appeared in some cells transfected with the wild-type gene and in cells transfected with mutants D145-262 or D414-433. Since the c-myc protein has been reported to stimulate expression of exogenous hsp70 protein, we also examined the intracellular distribution of hsp70 in the transfected cells. Double immunofluorescence microscopy revealed that hsp70 codistributed with the c-myc protein in distinct globules in the nucleus of many but not all myc-positive cells. However, the levels of hsp70 transcripts were not significantly raised compared to nontransfected and vector-transfected cells. Likewise, the levels of hsp70 protein did not vary significantly. These findings indicate that overexpression of c-myc stimulates translocation of preexisting hsp70 from the cytoplasm into the nucleus, rather than influencing hsp70 expression. Conceivably, this may represent one of several mechanisms whereby the cell deals with excessive amounts of c-myc protein.

Animals↗
PubMed1996

Molecular analyses of liver tumors in c-myc transgenic mice and c-myc and TGF-alpha double transgenic mice.

It has been demonstrated that co-expression of c-myc and transforming growth factor alpha (TGF-alpha) as transgenes in the mouse liver results in a tremendous acceleration of neoplastic development in this organ as compared to expression of either transgene alone [Murakami, H., et al. (1993) Cancer Res., 53, 1719-1723]. In order to clarify the roles of transgenes and additional other genetic alterations during hepatocarcinogenesis, we analyzed liver tumors developed in albumin/c-myc transgenic mice and albumin/c-myc and MT-1/TGF-alpha double transgenic mice. High expression of TGF-alpha transgene was found in nine of 14 (64%) liver tumors in double transgenic mice, suggesting that TGF-alpha overexpression confers growth advantage during hepatocarcinogenesis. Only one of 14 (7%) liver tumors in double transgenic mice and none of 13 liver tumors in c-myc transgenic mice showed overexpression of insulin-like growth factor II (IGF-II). This result was in contrast to the report by Takagi et al. [Takagi, H., et al. (1992) Cancer Res., 52, 5171-5177] which showed overexpression of IGF-II in 75% of liver tumors in TGF-alpha transgenic mice and suggested that the presence of c-myc transgenes together with TGF-alpha from an early stage of hepatocarcinogenesis may lead to different carcinogenic pathways which are independent of IGF-II overexpression. Expression of c-myc transgene was found in most of the liver tumors, but at lower levels than non-tumorous parts of the liver in c-myc and double transgenic mice. These results suggest that c-myc transgene expression cooperates with TGF-alpha in the early stages of hepatocarcinogenesis but has growth disadvantage in later stages of hepatocarcinogenesis. There was no evidence of mutational activation of the H-ras gene or mutational inactivation of the p53 gene in any liver tumors developed in c-myc or double transgenic mice.

Animals↗
PubMed2002

Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression.

To explore the role of c-Myc in carcinogenesis, we have developed a reversible transgenic model of pancreatic beta cell oncogenesis using a switchable form of the c-Myc protein. Activation of c-Myc in adult, mature beta cells induces uniform beta cell proliferation but is accompanied by overwhelming apoptosis that rapidly erodes beta cell mass. Thus, the oncogenic potential of c-Myc in beta cells is masked by apoptosis. Upon suppression of c-Myc-induced beta cell apoptosis by coexpression of Bcl-x(L), c-Myc triggers rapid and uniform progression into angiogenic, invasive tumors. Subsequent c-Myc deactivation induces rapid regression associated with vascular degeneration and beta cell apoptosis. Our data indicate that highly complex neoplastic lesions can be both induced and maintained in vivo by a simple combination of two interlocking molecular lesions.

3T3 Cells↗
PubMed1998

c-myc null cells misregulate cad and gadd45 but not other proposed c-Myc targets.

We report here that the expression of virtually all proposed c-Myc target genes is unchanged in cells containing a homozygous null deletion of c-myc. Two noteworthy exceptions are the gene cad, which has reduced log phase expression and serum induction in c-myc null cells, and the growth arrest gene gadd45, which is derepressed by c-myc knockout. Thus, cad and gadd45 are the only proposed targets of c-Myc that may contribute to the dramatic slow growth phenotype of c-myc null cells. Our results demonstrate that a loss-of-function approach is critical for the evaluation of potential c-Myc target genes.

Animals↗
PubMed1992

Expression of N-myc, c-myc, and MDR-1 proteins in newly established neuroblastoma cell lines: a study by immunofluorescence staining and flow cytometry.

A methodology for rapid isolation of neuroblastoma cells from marrow with metastatic neuroblastoma cells was developed using a cocktail of five antibodies and magnetic microspheres coated with secondary antibodies. Cells bound to microspheres were released by brief exposure to chymopapain, followed by repeated culture of released cells in serum-supplemented Dulbecco's modified Eagle's medium and selection for adherent cells. Using this methodology, over 35 primary cell lines were obtained free of contaminating normal cells. Detailed analyses of over 14 cell lines revealed gross differences in cell phenotype, size, morphology development of neurite processes, and doubling time (40 to 80 h). All cell lines expressed the M(r) 145,000 neurofilament, and a few expressed the M(r) 200,000 neurofilament, with very little or no expression of the M(r) 68,000 neurofilament. Eight % of all cells lines had near-diploid DNA content. High expression of the MDR-1 protein was detected in six of the 22 cell lines tested. Great heterogeneity was observed in the expression of N-myc oncoprotein, with ten of 13 patients overexpressing the protein. c-myc oncoprotein was also expressed in all cell lines; however, the level of expression was 4- to 10-fold lower than the N-myc oncoprotein. Localization studies of c-myc and N-myc oncoproteins on the level of light microscopy and electron microscopy revealed exclusive nuclear localization of c-myc, whereas N-myc was localized to the nucleus and to the cytoplasm.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Infrequent alteration of the c-myc gene in human glial tumours associated with increased numbers of c-myc positive cells.

Twenty five human glial tumours of different grades of malignancy were examined by Southern blotting and polymerase chain reaction (PCR) for alterations (rearrangements, amplification and deletions) in the c-myc gene. Number of c-myc positive cells per thousand cells were also counted in all the tumours after immunohistochemical staining for c-myc protein was done on fixed sections of the tumours. No tumours exhibited any amplification of the gene, as found by Southern blotting. One astrocytoma and one mixed glioma showed some rearrangements in the 3' end of the gene, as detected by Southern blotting and hydridization. These two tumours had higher number of c-myc positive cells than in other tumours of the same histopathological groups. Deletion in the first promoter region, as determined by PCR, was seen in only one astrocytoma. However, the number of c-myc positive cells in that tumour did not show any deviation from that found in other astrocytomas. In light of present literature, it is speculated that the 3' rearrangements may be the cause of increased number of c-myc immunopositive cells in those tumours by disrupting the 3' end of the gene leading to increased c-myc mRNA stability. Such a mechanism may play a part in small subset of glial and possibly other tumours.

Base Sequence↗
PubMed1998

Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence.

c-Myc is a nuclear protein with important roles in cell transformation, cell proliferation, and gene transcription. It has been previously shown that a 14-amino acid (aa) modified peptide (H1-S6A,F8A) derived from the helix 1 (H1) carboxylic region of c-Myc can interfere in vitro with specific c-Myc DNA binding. Here, we have linked the above Myc-derived 14-aa peptide to a 16-aa sequence from the third helix of Antennapedia (Int). It has been repeatedly reported that this 16-aa Antennapedia peptide is able to cross mammalian cell membranes and to work as a vector for short peptides. Using fluorescent (dansylated or rhodaminated) peptides, we have shown that the fusion peptide with the Antennapedia fragment (Int-H1-S6A,F8A) but not the c-Myc derived fragment alone (H1-S6A,F8A) was capable of internalization inside MCF-7 human breast cancer cells. Int-H1-S6A,F8A and H1-S6A,F8A were the only two peptides capable of inhibiting coimmunoprecipitation of the c-Myc/Max heterodimer in vitro. We have treated (continuously for 10-11 days) MCF-7 cells with four different peptides: Int, H1-S6A,F8A, Int-H1-S6A,F8A, and Int-H1wt [a peptide differing from Int-H1-S6A,F8A by 2 aa (S6 and F8) in the H1 region]. In intact MCF-7 cells, Int-H1-S6A,F8A was the only active peptide capable of inducing the following biological effects: (a) inhibition of cloning efficiency on plates; (b) inhibition of cell growth and induction of apoptosis in subconfluent/confluent cells; and (c) inhibition of transcription of two c-Myc-regulated genes (ODC and p53). Int-H1-S6A,F8A was active in the 1-10 microM range. Int-H1-S6A,F8A may represent a lead molecule for peptidomimetic compounds that have a similar three-dimensional structure but are more resistant to peptidases and, therefore, suitable for in vivo treatment of experimentally induced tumors.

Amino Acid Sequence↗
PubMed2003

Association of C-MYC amplification with progression from the in situ to the invasive stage in C-MYC-amplified breast carcinomas.

Human carcinoma in situ of the breast already demonstrates genomic changes found in invasive lesions. However, no specific genetic alterations have previously been identified that are associated with progression from the in situ to the invasive stage. By comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of an invasive breast carcinoma with a large associated in situ component, high-level amplification of C-MYC was found in the invasive component only. To determine the frequency of this correlation in a panel of 188 invasive breast carcinomas, 18 additional cases with C-MYC amplification were identified. Nine of these cases had a detectable adjacent in situ component. FISH analysis demonstrated increased (>5) C-MYC signals per nucleus in seven invasive components and increased (>4) C-MYC/centromere 8 signal ratios in five of these. None of the associated in situ components demonstrated these increases. The minimal amplified region was defined at 8q24.13-8qter. C-MYC amplification was correlated with overexpression of C-MYC and two of its target genes, TERT and FBL. Thus, C-MYC amplification is the first identified genetic alteration that is associated with progression from the in situ to the invasive stage of breast carcinoma.

Adult↗
PubMed1996

Reduced growth capacity of hepatocytes from c-myc and c-myc/TGF-alpha transgenic mice in primary culture.

We have previously shown that coexpression of c-myc and TGF-alpha in the liver results in accelerated replicative senescence and promotes tumor development in young adult transgenic mice. Here we describe the characteristics of hepatocyte proliferation in primary cultures established from 10-week-old control, c-myc and c-myc/TGF-alpha transgenic mice. A variety of cellular and functional changes occurred in the transgenic livers at this age including enhanced polypoidization and impairment of hepatic functions. Control mouse hepatocytes demonstrated a high level of DNA synthesis in serum-free medium with a maximum at day three in culture at which time 70% of the cells were in S phase. In contrast, DNA synthesis peaked one day later and was reduced by 50% in the cultured c-myc and c-myc/TGF-alpha hepatocytes. Also, higher frequency of apoptosis was observed in the transgenic hepatocytes. However, in hepatocytes isolated from c-myc/TGF-alpha mice, which show early appearance of preneoplastic lesions in vivo, the DNA synthesis continued for 6 days in culture in contrast to a sharp decrease in the labeling index of control and c-myc hepatocytes after 3-4 days in culture. The results suggest that proliferative features of the transgenic hepatocytes in vitro reflect the general properties of these cells in vivo and thus may provide a model for studies on senescence and transformation of hepatocytes.

Animals↗
PubMed1994

Hypersomy of chromosome 15 with retrovirally rearranged c-myc, loss of germline c-myc and IgK/c-myc juxtaposition in a macrophage-monocytic tumour line.

From a lymphoid tumour induced by 7,12-dimethylbenz-[a]-anthracene (DMBA) + methyl-N-nitrose-N-urea (MNU) in an [AKR Rb(6.15) x CBAT6T6]F1 mouse, a macrophage- monocyte line (KT-10) was isolated. Following ethyl methanesulfonate (EMS) treatment, a bromodeoxyuridine (BUdR) resistant subline was selected. Serial propagation of this line in vitro in the presence of BUdR (28 months) with periodic cytogenetic and molecular examinations, has led to the definition of four successive stages. During stage I, the cells were trisomic for chromosome 15. They contained Rb(6.15) and Rb(del6.15) of AKR and T(14;15) of CBA origin. Southern blotting showed the presence of both germline (G) and rearranged (R) c-myc. At stage II, Rb(del6.15) has duplicated. Both Rb(6.15) and T(14;15) persisted together with G-myc and R-myc. In stage III, the CBA-derived T(14;15) was lost, in parallel with G-myc. At this stage, a Dic.In(6.15) was detected. One of its arms was cytogenetically identical with the long arm of In(6.15) in the variant IgK/myc translocations. This chromosome carried R-myc and IgK in juxtaposition, as indicated by comigration on pulsed field electrophoresis (PFGE). At stage IV, the R-myc carrying AKR-derived chromosome 15s were present in six copies. Possible relationships between the increasing R/G myc ratio and changed growth characteristics in vivo and in vitro are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1988

Human promyelocytic leukemia HL-60 cell proliferation and c-myc protein expression are inhibited by an antisense pentadecadeoxynucleotide targeted against c-myc mRNA.

The human promyelocytic leukemia cell line HL-60 overexpresses the c-myc protooncogene. A calculated secondary structure for c-myc mRNA placed the initiation codon in a bulge of a weakly base-paired region. Treatment of HL-60 cells with 5' d(AACGTTGAGGGGCAT) 3', complementary to the initiation codon and the next four codons of c-myc mRNA, inhibited c-myc protein expression in a dose-dependent manner. However, treatment of HL-60 cells with 5' d(TTGGGATAACACTTA) 3', complementary to nucleotides 17-31 of vesicular stomatitis virus matrix protein mRNA, displayed no such effects. These results agree with analogous studies of normal human T lymphocytes [Heikkila, R., Schwab, G., Wickstrom, E., Loke, S. L., Pluznik, D. H., Watt, R. & Neckers, L. M. (1987) Nature (London) 328, 445-449], except that only one-third as much oligomer was needed for a comparable effect. Proliferation of HL-60 cells in culture was inhibited in a sequence-specific, dose-dependent manner by the c-myc-complementary oligomer, but neither the oligomer complementary to vesicular stomatitis virus matrix protein mRNA nor 5' d(CATTTCTTGCTCTCC) 3', complementary to nucleotides 5399-5413 of human immunodeficiency virus tat gene mRNA, inhibited proliferation. It thus appears that antisense oligodeoxynucleotides added to myc-transformed cells via culture medium are capable of eliciting sequence-specific, dose-dependent inhibition of c-myc protein expression and cell proliferation.

Base Sequence↗
PubMed1996

YY1 and c-Myc associate in vivo in a manner that depends on c-Myc levels.

The c-Myc oncoprotein has previously been shown to associate with transcription regulator YY1 and to inhibit its activity. We show herein that endogenous c-Myc and YY1 associate in vivo and that changes in c-Myc levels, which accompany mitogenic stimulation or differentiation of cultured cells, affect the ratio of free to c-Myc-associated YY1. We have also investigated the mechanism by which association with c-Myc inhibits YY1's ability to regulate transcription. c-Myc does not block binding of YY1 to DNA. However, protein association studies suggest that c-Myc interferes with the ability of YY1 to contact basal transcription proteins TATA-binding protein and TFIIB.

3T3 Cells↗
PubMed2002

Pag, a putative tumor suppressor, interacts with the Myc Box II domain of c-Myc and selectively alters its biological function and target gene expression.

The highly conserved Myc Box II (MBII) domain of c-Myc is critically important for transformation and transcriptional regulation. A yeast two-hybrid screen identified Pag as a MBII-interacting protein. Pag, a member of the peroxiredoxin family, has been reported previously to bind to and inhibit the cytostatic properties of the c-Abl oncoprotein. We now show that Pag promotes increased cell size and confers a proapoptotic phenotype, two hallmark features of ectopic c-Myc overexpression. Pag and c-Myc also confer resistance to oxidative stress, a previously unrecognized property of the latter protein. In contrast, Pag inhibits tumorigenesis by c-Myc-overexpressing fibroblasts and causes a broad but selective loss of c-Myc target gene regulation. Pag is therefore an MBII-interacting protein that can either mimic or enhance some of the c-Myc properties while at the same inhibiting others. These features, along with the previously identified interaction with c-Abl, provide support for the idea that Pag functions as a tumor suppressor.

3T3 Cells↗
PubMed2004

Direct activation of HSP90A transcription by c-Myc contributes to c-Myc-induced transformation.

The c-myc proto-oncogene encodes a ubiquitous transcription factor involved in the control of cell growth and differentiation and implicated in inducing tumorigenesis. Understanding the function of c-Myc and its role in cancer depends upon the identification of c-Myc target genes. Heat shock protein 90 (HSP90) is involved in the folding of proteins such as signal transduction molecules (Src, Raf1, cdk4) and steroid receptors and in enhancing the activity of telomerase and nitric-oxide synthase. Here we show that c-Myc directly activates HSP90A transcription. c-Myc-mediated induction of HSP90A transcription occurs in different tissues, is independent of cell proliferation, and is mediated by a c-Myc binding site in the proximal promoter region of HSP90A gene. Overexpression of HSP90A in Rat1a cells induces transformation. Short interference RNA of HSP90A/Hsp86alpha reduces transformation activity in HeLa and RatMyc cells. These results indicate that by induction of HSP90A c-Myc may control the activity of multiple signal pathways involved in cellular transformation.

Agar↗
PubMed2004

Myc-ARF (alternate reading frame) interaction inhibits the functions of Myc.

The tumor suppressor protein ARF (alternate reading frame) inhibits MDM2 to stabilize and activate the functions of p53. Here we provide evidence for an additional activity of ARF that attenuates cell cycle progression independently of p53 activation. We show that ARF interacts with c-Myc independently of MDM2 or p53. Consequently, ARF relocalizes c-Myc from the nucleoplasm to the nucleolus. Binding and relocalization by ARF correlate with an inhibition of the c-Myc-activated transcription in both p53-positive and -negative cells. Using inducible cell lines, we show that the wild type ARF, but not a mutant, inhibits expression of the c-Myc-induced genes before inhibiting S phase. Moreover, ARF inhibits Myc-induced progression into S phase in cells lacking p53 or expressing a defective p53, indicating that ARF inhibits the S phase stimulatory function of c-Myc independently of p53. Our results strongly suggest that cMyc is a bona fide target of ARF and that ARF attenuates c-Myc independently of the ARF-p53 axis.

Alternative Splicing↗
PubMed1989

Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl.

Retroviral expression vectors carrying the tyrosine kinase oncogenes abl, fms, src, and trk abrogate the requirements of murine myeloid FDC-P1 cells for interleukin-3 (IL-3). Factor-independent clones constitutively express c-myc in the absence of IL-3, whereas in parental cultures c-myc transcription requires the presence of the ligand. To directly test the effect of a tyrosine kinase oncogene on c-myc expression, retroviral constructs containing three different temperature-sensitive mutants of v-abl were introduced into myeloid IL-3-dependent FDC-P1 and 32D cells. At the permissive temperature, clones expressing temperature-sensitive abl behaved like wild-type abl-containing cells in their growth properties and expressed c-myc constitutively. Temperature shift experiments demonstrated that both IL-3 abrogation and the regulation of c-myc expression correlated with the presence of functional v-abl. Induction of c-myc expression by reactivation of temperature-sensitive v-abl mimicked c-myc induction by IL-3 in that it did not require protein synthesis and occurred at the level of transcription, with effects on both initiation and a transcription elongation block. However, v-abl-regulated FDC-P1 cell growth differed from IL-3-regulated growth in that c-fos and junB, which are normally induced by IL-3, were not induced by activation of v-abl.

Animals↗
PubMed1999

[Specific activity of the promoter containing Myc-Max response elements in c-myc-overexpressing cells].

OBJECTIVE: To investigate the specific activity of a hybrid promoter which is constructed by replacing the third domain of herpes simplex virus (HSV) thymidine kinase (TK) promoter with the Myc-Max response elements. METHODS: Myc-Max response elements were ligated with a third domain-deleted HSV-TK promoter by cloning and subcloning PCR products. Then a luciferase-expressing plasmid, in which the luciferase gene was put under the control of hybrid promoter, was constructed and transfected transiently into the cell lines which had been demonstrated to be c-myc over- or low-expressing by Northern blot hybridization. The luciferase activities in these cells were detected. RESULTS: In c-myc over-expressing cells, the hybrid promoter (Mpr) led to high levels of (81,966 +/- 43,238) relative light units (RLUs) in PC-2 cells and (70,563 +/- 22,435) RLUs in PC-7 cells, which were 78- and 150-fold higher than those coming from the third domain-deleted TK promoter (Epr), and also 6.9- and 1.7-fold higher than the activities controlled by TK promoter. However, Mpr showed a very low activity in c-myc low-expressing cells, in which the luciferase activity was (431 +/- 73) RLUs, similar to (601 +/- 141) RLUs produced by Epr. CONCLUSION: The activity of hybrid promoter, which is composed of Myc-Max response elements and the third domain-deleted TK promoter, possesses cell-type specificity for c-myc-overexpressing cells.

Animals↗