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PubMed2000

Differential activity of conditional MYC and its variant MYC-S in human mortal fibroblasts.

We have explored the effects of the conditional MYC-estrogen receptor fusion protein, MYC-ERTM, in human mortal fibroblasts, WI38, on cell-cycle entry, apoptosis and gene expression. The results indicate that activation of MYC-ERTM in WI38 cells is sufficient to cause S phase entry of quiescent cells, which is preceded by phosphorylation of Rb and activation of the Cdk2-associated kinase. We also analysed the MYC protein variant, MYC-S, which lacks part of the transcriptional activation domain but includes the conserved MYC box II and 26 amino acids N-terminal to it. MYC-S was previously shown to promote proliferation and apoptosis of immortalized rodent cell lines. The results indicate that MYC-S has undetectable activity as an inducer of S phase or apoptosis of quiescent WI38 cells. However, Myc-S stimulates proliferation of WI38 cells in the presence of 10% fetal calf serum. Surprisingly, we found that MYC-S, previously considered solely a repressor of specific reporter genes, is instead a weak transactivator of endogenous target genes both in mortal and immortalized cells. In addition, MYC-S exhibit a weak repressor activity upon an endogenous target gene only in immortalized cells. MYC-S transcriptional properties suggest that MYC box II and the adjacent N-terminal amino acids, while not sufficient for full repression function, participate in transactivation of endogenous target genes.

CDC2-CDC28 Kinases↗
PubMed2002

Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127-189 of c-myc.

C-myc availability is central for its ability to serve as a regulator of cell growth and death. Here we study the regulation of c-myc protein stability and identify domains of c-myc that are important for its stabilization in response to stress kinases activated following selective stress conditions. UV-irradiation elicited an increase in c-myc protein levels, which could be attenuated by inhibitors of stress kinases but also by actinomycin D-inhibitor of transcription. Inhibition of protein synthesis results in a noticeable decrease in c-myc levels, further pointing to the short half-life of the protein. However, in combination with tumor necrosis factor-alpha (TNF-alpha), cycloheximide efficiently increases steady-state levels of c-myc, suggesting that selective stress conditions are required to increase c-myc protein stability. Expression of MEKK1, an upstream regulator of protein kinases that has been implicated in mediating the response to diverse stress conditions, also results in an efficient increase in the half-life of c-myc protein. To map c-myc domains that are responsive to stress kinases, we monitored changes in the level of c-myc deletion mutants following MEKK1 expression. Of the seven c-myc deletion mutants analysed, the domain spanning amino acids 127-189 was found to be required for MEKK1-dependent increase in c-myc stability. In all, the present study identifies a novel domain that is important for the regulation of c-myc stability by stress kinases in response to selective stress conditions.

Antineoplastic Agents↗
PubMed2006

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors.

To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were co-amplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

Carcinoma↗
PubMed2000

A combination treatment of c-myc antisense DNA with all-trans-retinoic acid inhibits cell proliferation by downregulating c-myc expression in small cell lung cancer.

The dysregulation of both c-myc expression and retinoid signaling pathways commonly occurs in small cell lung cancers (SCLC), frequently accompanying tumor relapse, and contributing to the poor prognosis of patients with SCLC. In this study, we investigated whether c-myc antisense oligodeoxynucleoside phosphorothioate (OPT) covering the translational initiation site of c-myc mRNA used in combination with all-trans-retinoic acid (RA) would be more effective than either agent alone in inhibiting the growth of an SCLC cell line, NCI-H82, overexpressing c-myc with amplification of this gene, and whether this combination could be an experimental therapeutic tool against SCLC. c-myc antisense OPT decreased c-myc expression in Northern and Western blot analyses, thus inducing 40% and 20% cell growth inhibition compared with scrambled and sense OPT and with scrambled four guanosine-containing OPT (p < 0.01, and p < 0.01, respectively). All-trans-RA also inhibited cell proliferation at the rate of 40% by downregulating c-myc expression. Having obtained these results, we tested the hymothesis that c-myc antisense OPT in combination with all-trans-RA may further reduce c-myc expression and lead to improved cell growth control. This combination showed a greater inhibition of cell proliferation than either agent given alone (p < 0.01) (60% inhibition of cell growth compared with treatment of control scrambled or sense OPT alone, p < 0.01) through enhanced downregulation of c-myc expression. In conclusion, c-myc antisense DNA in combination with other modalities for c-myc downregulation may represent an attractive gene regulation-based therapy of SCLC in the future. Further efforts, however, using new oligodeoxynucleotide analogs, specific interventions for DNA delivery into cells, and more potent therapeutic agents are required to increase the potentiation of c-myc downregulation and cell growth inhibition.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

N-myc transactivates RCC1 gene expression in rat fibroblast cells transformed by N-myc and v-ras.

Oncogenic cooperation was found between the N-myc and v-ras oncogenes in a rat fibroblast cell line, 3Y1. To investigate the specific role of N-myc in the transformation, we established transformed cell lines that expressed N-myc under a controllable promoter. Using these cells, we found that constitutive expression of N-myc is necessary to maintain the transformation, and that the expression level of N-myc is closely correlated with the transformation. Since another myc family gene, c-myc, directly activates expression of RCC1, which has important functions for eukaryotic cell proliferation, we focused on the relationship between N-myc and RCC1. Cells transformed by N-myc and v-ras expressed several times more RCC1 mRNA than the parent 3Y1 cells, and the expression of RCC1 changed in a parallel with the expression of N-myc. Gel retardation analysis and experiments with reporter plasmids constructed from a DNA fragment of the RCC1 gene indicated that the N-Myc protein controls expression of RCC1 by binding directly to CACGTG elements in the RCC1 gene. These results suggest that N-myc can directly transactivate expression of RCC1, a c-myc target gene.

Animals↗
PubMed1988

Elevated expression of c-myc and N-myc produces distinct changes in nuclear fine structure and chromatin organization.

The proto-oncogenes c-myc and N-myc encode nuclear phosphoproteins with unknown function. Here, c-myc or N-myc, or hybrid constructs of the two, were transfected into fibroblastic cells (CV-1) using SV40-based high expression vectors. The cells were studied by indirect immunofluorescence microscopy and transmission electron microscopy to determine the localization of the two myc proteins within the nucleus and their influence on nuclear fine structure and chromatin organization. In c-myc transfected cells the overproduced protein product accumulated in large amorphous globules that displaced the normal chromatin and did not stain for DNA. In N-myc transfected cells condensed chromatin loops were formed. They were attached to the nuclear envelope and by traction in the latter they may have contributed to give the nucleus its irregular shape in these cells. During mitosis the chromatin loops persisted as clearly identifiable entities within the chromosomes, suggesting a rigid conformation that did not allow normal chromosome packaging. These findings suggest that the c-myc and N-myc proteins bind to different structures and may have different functions. Observations on cells transfected with hybrid constructs indicated that both the second and third exon of c-myc were required to yield a product that behaved like the c-myc protein. In contrast, domains encoded by the second exon of N-myc were sufficient to give rise to a product that morphologically behaved like the N-myc protein.

Animals↗
PubMed1984

Inhibition of DNA binding of purified p55v-myc in vitro by antibodies against bacterially expressed myc protein and a synthetic peptide.

To identify viral myc proteins, we have prepared myc-specific antibodies: (i) against a synthetic peptide corresponding to the nine carboxy-terminal amino acids of the viral myc (C9); (ii) against a bacterially expressed viral myc protein obtained by inserting the SalI-BamHI fragment of the viral MC29 DNA clone in the expression vector pPLc24. Both antisera recognize a protein of 55 000 mol. wt., p55v-myc, in MH2- and OK10-transformed fibroblasts. The protein is located in the nucleus, as shown by indirect immunofluorescence and cell fractionation. Antibodies against the C9 peptide were used to purify the p55v-myc by immunoaffinity column purification (3000-fold) from OK10- and MH2-transformed fibroblasts. p55v-myc binds to double-stranded DNA in vitro as does p110gag-myc. DNA binding in vitro is inhibited by the immunoglobulin fraction of antibodies against the bacterially expressed myc protein. Furthermore, a synthetic peptide consisting of 16 amino acids (C16) was used to isolate specific immunoglobulins which also inhibit DNA binding in vitro. OK10 codes, in addition to p55v-myc, for a p200gag-pol-myc polyprotein. The majority of this protein is located in the cytoplasm (79%). The purified protein binds to single-stranded RNA in vitro, unlike other gag-myc or myc proteins.

Antibodies, Viral↗
PubMed1987

Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice.

Transgenic mice bearing a cellular myc oncogene coupled to the immunoglobulin heavy-chain enhancer (E mu) exhibit perturbed B-lymphocyte development and succumb to B lymphoid tumors. To investigate how the enhancer has affected myc expression, we analyzed the structure and abundance of myc transcripts in tissues of prelymphomatous mice and in the lymphomas. Expression of the E mu-myc transgene appeared to be confined largely to B lymphoid cells, being dominant in bone marrow, spleen, and lymph nodes, with no detectable expression in T cells or other hematopoietic lineages examined. The myc transcripts initiated very predominantly at the normal myc promoters, although use of the more upstream myc promoter was accentuated and an enhancer-associated promoter may be used infrequently. The level of E mu-myc transcripts in the preneoplastic lymphoid tissues and in the E mu-myc tumors was not markedly higher than myc RNA levels in proliferating normal lymphocytes. Thus, enforced expression of structurally normal myc transcripts at only a modestly elevated level has profound biological consequences. The absence of detectable endogenous c-myc RNA in any tumor, or in preneoplastic bone marrow, supports a negative feedback model for normal c-myc regulation.

Animals↗
PubMed1996

Dominant negative mutants of Myc inhibit cooperation of both Myc and adenovirus serotype-5 E1a with Ras.

We have used dominant negative Myc mutants to analyze the Myc and E1a mechanisms of cooperation with Ras. We show that mutants of Myc with an altered basic region (BR; RR366, 367EE) or deletion of the leucine zipper (LZ; delta aa 414-439), changes which modify the DNA binding domain, or with deletions in the Myc amino terminal conserved regions box 1 (dlMB1; delta aa 46-55) and box 2 (dlMB2; delta aa 132-140) inhibit cooperation of wt Myc and activated Ras to transform rat embryo fibroblasts (REF). Expression of the amino terminal 104 aa had no effect whereas wt Myc stimulated focus formation. Mutant dlMB1 cooperated with Ras with one half wt efficiency while dlMB2 was inactive. No mutant tested was toxic during neomycin cotransformation of REF to G418 resistance. Interestingly, these Myc mutants exerted a parallel inhibition of E1a-Ras cooperation to transform REF. This suggests that the Myc-Ras and E1a-Ras cooperation pathways intersect and require common protein factors. A Myc box 2 deletion mutant which is a wt transactivator of the Myc responsive ornithine decarboxylase promoter, but unlike the wt does not repress the adenovirus-2 core promoter (Li et al., 1994, EMBO J., 13:4070-4079), inhibits Myc-Ras and E1a-Ras cooperation. This suggests that a box 2-dependent step, potentially gene repression, is required for both the E1a- and Myc-Ras cooperation mechanisms.

Adenovirus E1A Proteins↗
PubMed1991

Nuclear colocalization of cellular and viral myc proteins with HSP70 in myc-overexpressing cells.

The c-myc oncogene and its viral counterpart v-myc encode phosphoproteins which have been located within cell nuclei, excluding nucleoli. We have expressed the c-myc gene under the simian virus 40 early promoter and studied the distribution of its protein product in transient expression assays in COS, HeLa, and 293 cells. We found three distinct patterns of c-myc immunofluorescence in the transfected cells: one-third of the c-myc-positive cells displayed a diffuse nuclear distribution, and in two-thirds of the cells the c-myc fluorescence was accumulated either in small amorphous or in large multilobed phase-dense nuclear structures. Unexpectedly, these structures also stained for the HSP70 heat shock protein in both heat-shocked and untreated cells. Our results indicate that both transient and stable overexpression of either the c-myc or v-myc protein induces translocation of the endogenous HSP70 protein from the cytoplasm to the nucleus, where it becomes sequestered in structures containing the myc protein. Interestingly, the closely related N-myc protein does not stimulate substantial nuclear expression of the HSP70 protein. Studies with chimeric myc proteins revealed that polypeptide sequences encoded by the second exon of c-myc are involved in colocalization with HSP70.

Animals↗
PubMed1995

A link between increased transforming activity of lymphoma-derived MYC mutant alleles, their defective regulation by p107, and altered phosphorylation of the c-Myc transactivation domain.

The c-Myc protein is a transcription factor with an N-terminal transcriptional regulatory domain and C-terminal oligomerization and DNA-binding motifs. Previous studies have demonstrated that p107, a protein related to the retinoblastoma protein, binds to the c-Myc transcriptional activation domain and suppresses its activity. We sought to characterize the transforming activity and transcriptional properties of lymphoma-derived mutant MYC alleles. Alleles encoding c-Myc proteins with missense mutations in the transcriptional regulatory domain were more potent than wild-type c-Myc in transforming rodent fibroblasts. Although the mutant c-Myc proteins retained their binding to p107 in in vitro and in vivo assays, p107 failed to suppress their transcriptional activation activities. Many of the lymphoma-derived MYC alleles contain missense mutations that result in substitution for the threonine at codon 58 or affect sequences flanking this amino acid. We observed that in vivo phosphorylation of Thr-58 was absent in a lymphoma cell line with a mutant MYC allele containing a missense mutation flanking codon 58. Our in vitro studies suggest that phosphorylation of Thr-58 in wild-type c-Myc was dependent on cyclin A and required prior phosphorylation of Ser-62 by a p107-cyclin A-CDK complex. In contrast, Thr-58 remained unphosphorylated in two representative mutant c-Myc transactivation domains in vitro. Our studies suggest that missense mutations in MYC may be selected for during lymphomagenesis, because the mutant MYC proteins have altered functional interactions with p107 protein complexes and fail to be phosphorylated at Thr-58.

Alleles↗
PubMed1991

Inhibition of c-myc expression by phosphorothioate antisense oligonucleotide identifies a critical role for c-myc in the growth of human breast cancer.

In search of critical genes in the mechanism of estrogen action in human breast cancer, we previously showed that estrogen stimulates transcription of the c-myc gene in estrogen-dependent (MCF-7) cells. We have now examined the role of c-myc in estrogen-stimulated growth of MCF-7 cells through the use of a synthetic antisense c-myc phosphorothioate oligonucleotide to specifically inhibit expression of the c-myc protein. Estrogen induces a 5-fold increase in c-myc protein expression within 90 min in steroid-deprived cells, as detected by Western blot. Prior exposure of MCF-7 cells to 10 microM c-myc antisense oligonucleotide results in up to 95% inhibition of the c-myc protein expression induced by estrogen. Antisense-myc oligonucleotide inhibits estrogen-stimulated cell growth by up to 75% over 9 days and also exerts a cytostatic effect on the growth of estrogen-independent MDA-MB-231 cells which show relatively high, constitutive expression of c-myc. Sense-myc and antisense-pS2 oligonucleotides have no effect on c-myc protein level or growth in either cell line. These results demonstrate both the specific and durable effects of antisense phosphorothioate oligonucleotides. Furthermore, these results indicate a critical role for c-myc in the growth of breast cancer cells and support the hypothesis that loss of estrogen regulation of this gene may be an important factor in the progression of breast cancer.

Base Sequence↗
PubMed1994

Dysfunction of the Myc-induced apoptosis mechanism accompanies c-myc activation in the tumorigenic L929 cell line.

Activation of the c-myc protooncogene, resulting in deregulated, over-expression of the c-Myc protein, can induce both cell proliferation and programmed cell death (apoptosis) in nontransformed cells. Yet, c-myc activation is commonly tolerated in many tumors. This apparent paradox can be resolved if activation of c-myc in transformed cells is associated with loss of Myc-induced apoptosis. To examine this hypothesis, we characterized both the mechanisms of c-myc activation and programmed cell death in the tumorigenic L929 cell line. We showed that activation of c-myc in the L929 cell line involves several distinct mechanisms, including dysfunction of the Myc autosuppression pathway and alteration of c-Myc protein expression. In addition, we demonstrated that L929 cells do not undergo Myc-induced apoptosis. Analysis of somatic cell hybrids revealed that this abrogation of programmed cell death can be partially restored and is likely due to one or more genetic lesions. Our results support the hypothesis that the dysfunction of the Myc-induced apoptosis mechanism can accompany c-myc activation and provide an in vivo example illustrating two cooperative events which can contribute to tumor progression.

Animals↗
PubMed2004

Kinetics of myc-max-mad gene expression during hepatocyte proliferation in vivo: Differential regulation of mad family and stress-mediated induction of c-myc.

Mad proteins (Mad1, Mxi1, Mad3, Mad4, Mnt/Rox) are biochemical and biological antagonists of c-Myc oncoprotein. Mad-Max dimers repress the transcription of the same target genes activated by Myc-Max dimers. Despite the critical role of Max and Mad proteins as modulators of c-Myc functions, there are no comparative data on their regulation in vivo. We carried out a systematic analysis of c-myc, max, and mad family expression in a model of synchronized cell proliferation in vivo in adult tissues, that is, rat hepatocytes after partial hepatectomy. We confirmed the previously reported early peak of c-myc expression after hepatectomy but we show that it did not correlate with hepatocyte proliferation as it also occurred in sham-operated animals as a result of surgical stresses. A second peak of c-myc expression was observed later, at the time of the wave of DNA synthesis. No such expression was detected in sham-operated rat quiescent hepatocytes. max expression increased around 4-16 h after hepatectomy, before the peaks of c-myc and DNA synthesis. mxi1 and mad4 were slightly downregulated during liver regeneration. mnt/rox expression did not change. These expression patterns suggest a role of Myc-Max for efficient mitogenic response of hepatocytes. We also analyzed the effects of Myc and Max ectopic expression on the clonogenic growth of the rat hepatoma cells. Expression of c-Myc and Max increased clonogenic growth, whereas the reduction of c-Myc levels by an antisense vector decreased growth. The results suggest nonredundant roles for mad genes in hepatocyte proliferation and point to c-Myc as a putative target for anticancer therapy of liver cancer.

Animals↗
PubMed2003

The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription.

The transcription regulatory oncoprotein c-Myc controls genes involved in cell growth, apoptosis, and oncogenesis. c-Myc is turned over very quickly through the ubiquitin/proteasome pathway. The proteins involved in this process are still unknown. We have found that Skp2 interacts with c-Myc and participates in its ubiquitylation and degradation. The interaction between Skp2 and c-Myc occurs during the G1 to S phase transition of the cell cycle in normal lymphocytes. Surprisingly, Skp2 enhances c-Myc-induced S phase transition and activates c-Myc target genes in a Myc-dependent manner. Further, Myc-induced transcription was shown to be Skp2 dependent, suggesting interdependence between c-Myc and Skp2 in activation of transcription. Moreover, Myc-dependent association of Skp2, ubiquitylated proteins, and subunits of the proteasome to a c-Myc target promoter was demonstrated in vivo. The results suggest that Skp2 is a transcriptional cofactor for c-Myc and indicates a close relationship between transcription activation and transcription factor ubiquitination.

Animals↗
PubMed2002

Guanine nucleotide exchange factor, Tiam1, directly binds to c-Myc and interferes with c-Myc-mediated apoptosis in rat-1 fibroblasts.

The transcription factor c-Myc is important for the control of cell growth, cell cycle progression, neoplasia, and apoptotic cell death. Recently, c-Myc-binding proteins, which bind either to the N-terminal domain or the C-terminal domain of c-Myc, have been proposed as the key molecules to realize the mechanisms of these multiple c-Myc functions. We report in the present study on another protein, Tiam1, which is a specific guanine nucleotide exchange factor of Rac1 and which binds to c-Myc and modulates several of its biological functions. We were able to detect the direct binding and in vivo association between c-Myc and Tiam1. The necessary role in this interaction of the Myc box II of c-Myc was revealed in the cell extracts. The additional discovery of the intranuclear localization of Tiam1 in Rat1 cells and in neuronal cells of the mouse brain suggests this interaction may occur in the nucleus. Overexpression of Tiam1 repressed the luciferase activity of c-Myc and also inhibited the c-Myc apoptotic activity through this protein-protein interaction. Taken together, we concluded that Tiam1 is another c-Myc regulator, working in the nuclei to control c-Myc-related apoptosis.

Animals↗
PubMed1989

Coamplification of the L-myc and N-myc oncogenes in a neuroblastoma cell line.

The L-myc, N-myc and c-myc genes are members of the myc oncogene family. In particular, L-myc is novel, and amplification of L-myc is still unknown except in small cell lung carcinoma. We examined L-myc amplification in 30 human neuroblastomas using Southern blot hybridization, and found that the L-myc gene was amplified approximately 5-fold in GOTO, a human neuroblastoma cell line. The N-myc gene was also amplified approximately 60-fold and furthermore, over-expression of L-myc and N-myc genes was observed in this cell line. In this report, we describe the coamplification of the myc gene family in the GOTO neuroblastoma cell line.

Blotting, Southern↗
PubMed2001

Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis.

The ARF and p53 tumor suppressors mediate Myc-induced apoptosis and suppress lymphoma development in E mu-myc transgenic mice. Here we report that the proapoptotic Bcl-2 family member Bax also mediates apoptosis triggered by Myc and inhibits Myc-induced lymphomagenesis. Bax-deficient primary pre-B cells are resistant to the apoptotic effects of Myc, and Bax loss accelerates lymphoma development in E mu-myc transgenics in a dose-dependent fashion. Eighty percent of lymphomas arising in wild-type E mu-myc transgenics have alterations in the ARF-Mdm2-p53 tumor suppressor pathway characterized by deletions in ARF, mutations or deletions of p53, and overexpression of Mdm2. The absence of Bax did not alter the frequency of biallelic deletion of ARF in lymphomas arising in E mu-myc transgenic mice or the rate of tumorigenesis in ARF-null mice. Furthermore, Mdm2 was overexpressed at the same frequency in lymphomas irrespective of Bax status, suggesting that Bax resides in a pathway separate from ARF and Mdm2. Strikingly, lymphomas from Bax-null E mu-myc transgenics lacked p53 alterations, whereas 27% of the tumors in Bax(+/-) E mu-myc transgenic mice contained p53 mutations or deletions. Thus, the loss of Bax eliminates the selection of p53 mutations and deletions, but not ARF deletions or Mdm2 overexpression, during Myc-induced tumorigenesis, formally demonstrating that Myc-induced apoptotic signals through ARF/Mdm2 and p53 must bifurcate: p53 signals through Bax, whereas this is not necessarily the case for ARF and Mdm2.

Animals↗