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Variant Max protein, derived by alternative splicing, associates with c-Myc in vivo and inhibits transactivation.
Arsura M, Deshpande A, Hann SR, Sonenshein GE
(1995) Mol Cell Biol 15: 6702-9
MeSH Terms: 3T3 Cells, Alternative Splicing, Amino Acid Sequence, Animals, Base Sequence, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic-Leucine Zipper Transcription Factors, Blotting, Western, Cell Line, Cell Nucleus, DNA Primers, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Helix-Loop-Helix Motifs, Humans, Mice, Molecular Sequence Data, Molecular Weight, Plasmids, Polymerase Chain Reaction, Proto-Oncogene Proteins c-myc, Recombinant Fusion Proteins, Transcription Factors, Transcriptional Activation
Show Abstract · Added March 20, 2014
Max (Myc-associated factor X) is a basic helix-loop-helix/leucine zipper protein that has been shown to play a central role in the functional activity of c-Myc as a transcriptional activator. Max potentiates the binding of Myc-Max heterodimers through its basic region to its specific E-box Myc site (EMS), enabling c-Myc to transactivate effectively. In addition to the alternatively spliced exon a, several naturally occurring forms of alternatively spliced max mRNAs have been reported, but variant protein products from these transcripts have not been detected. Using Western blot (immunoblot) and immunoprecipitation analysis, we have identified a variant form of Max protein (16 to 17 kDa), termed dMax, in detergent nuclear extracts of murine B-lymphoma cells, normal B lymphocytes, and NIH 3T3 fibroblasts. Cloning and sequencing revealed that dMax contains a deletion spanning the basic region and helix 1 and the loop of the helix-loop-helix region, presumably as a result of alternative splicing of max RNA. S1 nuclease analysis confirmed the presence of the mRNA for dMax in cells. The dMax protein, prepared via in vitro transcription and translation, associated with bacterially synthesized Myc-glutathione S-transferase. Coimmunoprecipitation of dMax and c-Myc indicated their intracellular association. In vitro-synthesized dMax failed to bind EMS DNA, presumably because of the absence of the basic region. Coexpression of dMax inhibited EMS-mediated transactivation by c-Myc. Thus dMax, which can interact with c-Myc, appears to function as a dominant negative regulator, providing an additional level of regulation to the transactivation potential of c-Myc.
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24 MeSH Terms
Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1.
Roussel MF, Davis JN, Cleveland JL, Ghysdael J, Hiebert SW
(1994) Oncogene 9: 405-15
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, Cell Cycle Proteins, Cell Line, DNA, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, Electrophoresis, Fibroblasts, Gene Expression Regulation, Genes, myc, Mice, Molecular Sequence Data, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Protein c-ets-1, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ets, Proto-Oncogene Proteins c-myc, Retinoblastoma-Binding Protein 1, S Phase, Transcription Factor DP1, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Transfection
Show Abstract · Added June 10, 2010
NIH3T3 cells expressing a mutant colony-stimulating factor-1 receptor (CSF-1R) containing a phenylalanine for tyrosine substitution in the tyrosine kinase domain at codon 809 exhibit defective myc regulation and do not enter S phase when stimulated by CSF-1. Enforced expression of either ets-1 or ets-2 in these cells restores their mitogenic response, albeit less efficiently than myc itself, suggesting that ets proteins may regulate c-myc expression. Ets-1 transactivates reporter genes driven by the human and mouse c-myc promoters through the binding site for the transcription factor E2F, the latter being required for E1A- and serum-induced c-myc expression. Analysis of E2F-1 sequences identified a minimal DNA binding domain that is related to those of ets proteins. Although E2F and ets proteins interact with similar consensus DNA binding sites, in vitro binding assays revealed that E2F can bind DNA as a homodimer, whereas ets proteins bind these sites as monomers. E2F and ets proteins do not form heterodimers in vitro and do not transactivate c-myc synergistically. Thus, E2F-1 and ets family members may independently regulate c-myc transcription through the same binding site at different times following growth factor stimulation.
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29 MeSH Terms
Binding of TFIID and MEF2 to the TATA element activates transcription of the Xenopus MyoDa promoter.
Leibham D, Wong MW, Cheng TC, Schroeder S, Weil PA, Olson EN, Perry M
(1994) Mol Cell Biol 14: 686-99
MeSH Terms: Animals, Base Sequence, Binding Sites, Cell Differentiation, DNA, DNA-Binding Proteins, MEF2 Transcription Factors, Molecular Sequence Data, Muscles, Mutagenesis, MyoD Protein, Myogenic Regulatory Factors, Promoter Regions, Genetic, Sequence Homology, Nucleic Acid, TATA Box, Tissue Distribution, Transcription Factor TFIID, Transcription Factors, Transcriptional Activation, Xenopus laevis
Show Abstract · Added March 5, 2014
Members of the MyoD family of helix-loop-helix proteins control expression of the muscle phenotype by regulating the activity of subordinate genes. To investigate processes that control the expression of myogenic factors and regulate the establishment and maintenance of the skeletal muscle phenotype, we have analyzed sequences necessary for transcription of the maternally expressed Xenopus MyoD (XMyoD) gene. A 3.5-kb DNA fragment containing the XMyoDa promoter was expressed in a somite-specific manner in injected frog embryos. The XMyoDa promoter was active in oocytes and cultured muscle cells but not in fibroblasts or nonmuscle cell lines. A 58-bp fragment containing the transcription initiation site, a GC-rich region, and overlapping binding sites for the general transcription factor TFIID and the muscle-specific factor MEF2 was sufficient for muscle-specific transcription. Transcription of the minimal XMyoDa promoter in nonmuscle cells was activated by expression of Xenopus MEF2 (XMEF2) and required binding of both MEF2 and TFIID to the TATA motif. These results demonstrate that the XMyoDa TATA motif is a target for a cell-type-specific regulatory factor and suggests that MEF2 stabilizes and amplifies XMyoDa transcription in mesodermal cells committed to the muscle phenotype.
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20 MeSH Terms
c-jun inhibits transcriptional activation by the insulin enhancer, and the insulin control element is the target of control.
Henderson E, Stein R
(1994) Mol Cell Biol 14: 655-62
MeSH Terms: Animals, Base Sequence, Binding Sites, Cell Line, DNA, Enhancer Elements, Genetic, Genes, jun, Helix-Loop-Helix Motifs, Humans, Insulin, Islets of Langerhans, Molecular Sequence Data, Proto-Oncogene Proteins c-jun, Rabbits, Rats, Transcription, Genetic, Transcriptional Activation
Show Abstract · Added December 10, 2013
Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located between nucleotides -340 and -91 relative to the transcription start site. One of the principal control elements within the enhancer is found between nucleotides -100 and -91 (GCCATCTGCT, referred to as the insulin control element [ICE]) and is regulated by both positive- and negative-acting transcription factors in the helix-loop-helix (HLH) family. It was previously shown that the c-jun proto-oncogene can repress insulin gene transcription. We have found that c-jun inhibits ICE-stimulated transcription. Inhibition of ICE-directed transcription is mediated by sequences within the carboxy-terminal region of the protein. These c-jun sequences span an activation domain and the basic leucine zipper DNA binding-dimerization region of the protein. Both regions of c-jun are conserved within the other members of the jun family: junB and junD. These proteins also suppress ICE-mediated transcription. The jun proteins do not appear to inhibit insulin gene transcription by binding directly to the ICE. c-jun and junB also block the trans-activation potential of two skeletal muscle-specific HLH proteins, MyoD and myogenin. These results suggests that the jun proteins may be common transcription control factors used in skeletal muscle and pancreatic beta cells to regulate HLH-mediated activity. We discuss the possible significance of these observations to insulin gene transcription in pancreatic beta cells.
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17 MeSH Terms
Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-Myc protein is regulated by mitogens and in mitosis.
Lutterbach B, Hann SR
(1994) Mol Cell Biol 14: 5510-22
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Cell Nucleus, Chick Embryo, Coturnix, Cytoplasm, Mitogens, Mitosis, Molecular Sequence Data, Phosphorylation, Phosphoserine, Phosphothreonine, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-myc, Transcriptional Activation
Show Abstract · Added March 5, 2014
The N-terminal domain of the c-Myc protein has been reported to be critical for both the transactivation and biological functions of the c-Myc proteins. Through detailed phosphopeptide mapping analyses, we demonstrate that there is a cluster of four regulated and complex phosphorylation events on the N-terminal domain of Myc proteins, including Thr-58, Ser-62, and Ser-71. An apparent enhancement of Ser-62 phosphorylation occurs on v-Myc proteins having a mutation at Thr-58 which has previously been correlated with increased transforming ability. In contrast, phosphorylation of Thr-58 in cells is dependent on a prior phosphorylation of Ser-62. Hierarchical phosphorylation of c-Myc is also observed in vitro with a specific glycogen synthase kinase 3 alpha, unlike the promiscuous phosphorylation observed with other glycogen synthase kinase 3 alpha and 3 beta preparations. Although both p42 mitogen-activated protein kinase and cdc2 kinase specifically phosphorylate Ser-62 in vitro and cellular phosphorylation of Thr-58/Ser-62 is stimulated by mitogens, other in vivo experiments do not support a role for these kinases in the phosphorylation of Myc proteins. Unexpectedly, both the Thr-58 and Ser-62 phosphorylation events, but not other N-terminal phosphorylation events, can occur in the cytoplasm, suggesting that translocation of the c-Myc proteins to the nucleus is not required for phosphorylation at these sites. In addition, there appears to be an unusual block to the phosphorylation of Ser-62 during mitosis. Finally, although the enhanced transforming properties of Myc proteins correlates with the loss of phosphorylation at Thr-58 and an enhancement of Ser-62 phosphorylation, these phosphorylation events do not alter the ability of c-Myc to transactivate through the CACGTG Myc/Max binding site.
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16 MeSH Terms
The alternatively initiated c-Myc proteins differentially regulate transcription through a noncanonical DNA-binding site.
Hann SR, Dixit M, Sears RC, Sealy L
(1994) Genes Dev 8: 2441-52
MeSH Terms: Amino Acid Sequence, Animals, Avian Sarcoma Viruses, Base Sequence, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Basic-Leucine Zipper Transcription Factors, Binding Sites, Cell Division, Cell Line, DNA, DNA-Binding Proteins, Enhancer Elements, Genetic, HeLa Cells, Humans, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Peptide Chain Initiation, Translational, Protein Biosynthesis, Proto-Oncogene Proteins c-myc, Repetitive Sequences, Nucleic Acid, Transcription Factors, Transcription, Genetic, Transcriptional Activation
Show Abstract · Added March 5, 2014
The myc proto-oncogene family has been implicated in multiple cellular processes, including proliferation, differentiation, and apoptosis. The Myc proteins, as heterodimers with Max protein, have been shown to function as activators of transcription through an E-box DNA-binding element, CACGTG. We have now found that the c-Myc proteins regulate transcription through another, noncanonical, DNA sequence. The non-AUG-initiated form of the c-Myc protein, c-Myc 1, strongly and specifically activates transcription of the C/EBP sequences within the EFII enhancer element of the Rous sarcoma virus long terminal repeat. In contrast, comparable amounts of the AUG-initiated form, c-Myc 2, fail to significantly affect enhancer activity. However, both c-Myc proteins trans-activate the CACGTG sequence comparably. In addition, Myc/Max heterodimers, but not Max homodimers, bind to the EFII enhancer sequence in vitro. Finally, c-Myc 1 overexpression, but not c-Myc 2 overexpression, significantly inhibits cell growth. These results reveal new transcriptional activities for the Myc proteins and demonstrate that the different forms of the Myc protein are functionally distinct. These results also suggest an interplay between two different growth regulatory transcription factor families.
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24 MeSH Terms
Isolation and characterization of a novel transcription factor that binds to and activates insulin control element-mediated expression.
Robinson GL, Cordle SR, Henderson E, Weil PA, Teitelman G, Stein R
(1994) Mol Cell Biol 14: 6704-14
MeSH Terms: Amino Acid Sequence, Base Sequence, Cell Compartmentation, Cloning, Molecular, DNA-Binding Proteins, Gene Expression Regulation, Humans, Inhibitor of Differentiation Protein 1, Insulin, Insulinoma, Molecular Sequence Data, Nuclear Proteins, Organ Specificity, Pancreas, Pancreatic Neoplasms, Protein Binding, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Sequence Analysis, DNA, Sequence Homology, Amino Acid, TCF Transcription Factors, Trans-Activators, Transcription Factor 7-Like 1 Protein, Transcription Factors, Transcriptional Activation
Show Abstract · Added December 10, 2013
Pancreatic beta-cell-type-specific transcription of the insulin gene is principally regulated by a single cis-acting DNA sequence element, termed the insulin control element (ICE), which is found within the 5'-flanking region of the gene. The ICE activator is a heteromeric complex composed of an islet alpha/beta-cell-specific factor associated with the ubiquitously distributed E2A-encoded proteins (E12, E47, and E2-5). We describe the isolation and characterization of a cDNA for a protein present in alpha and beta cells, termed INSAF for insulin activator factor, which binds to and activates ICE-mediated expression. INSAF was isolated from a human insulinoma cDNA library. Transfection experiments demonstrated that INSAF activates ICE expression in insulin-expressing cells but not in non-insulin-expressing cells. Cotransfection experiments showed that activation by INSAF was inhibited by Id, a negative regulator of basic helix-loop-helix (bHLH) protein function. INSAF was also shown to associate in vitro with the bHLH protein E12. In addition, affinity-purified INSAF antiserum abolished the formation of the activator-specific ICE-binding complex. Immunohistochemical studies indicate that INSAF is restricted in terms of its expression pattern, in that INSAF appears to be detected only within the nuclei of islet pancreatic alpha and beta cells. All of these data are consistent with the proposal that INSAF is either part of the ICE activator or is antigenically related to the specific activator required for insulin gene transcription.
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The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation.
Meyers S, Lenny N, Hiebert SW
(1995) Mol Cell Biol 15: 1974-82
MeSH Terms: Alternative Splicing, Amino Acid Sequence, Base Sequence, Cell Compartmentation, Cell Nucleus, Cloning, Molecular, Consensus Sequence, Core Binding Factor Alpha 2 Subunit, Core Binding Factors, DNA, Complementary, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemia, Myeloid, Acute, Molecular Sequence Data, Neoplasm Proteins, Protein Binding, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Recombinant Fusion Proteins, Transcription Factors, Transcription, Genetic, Transcriptional Activation
Show Abstract · Added June 10, 2010
The AML-1/CBF beta transcription factor complex is targeted by both the t(8;21) and the inv(16) chromosomal alterations, which are frequently observed in acute myelogenous leukemia. AML-1 is a site-specific DNA-binding protein that recognizes the enhancer core motif TGTGGT. The t(8;21) translocation fuses the first 177 amino acids of AML-1 to MTG8 (also known as ETO), generating a chimeric protein that retains the DNA-binding domain of AML-1. Analysis of endogenous AML-1 DNA-binding complexes suggested the presence of at least two AML-1 isoforms. Accordingly, we screened a human B-cell cDNA library and isolated a larger, potentially alternatively spliced, form of AML1, termed AML1B. AML-1B is a protein of 53 kDa that binds to a consensus AML-1-binding site and complexes with CBF beta. Subcellular fractionation experiments demonstrated that both AML-1 and AML-1/ETO are efficiently extracted from the nucleus under ionic conditions but that AML-1B is localized to a salt-resistant nuclear compartment. Analysis of the transcriptional activities of AML-1, AML-1B, and AML-1/ETO demonstrated that only AML-1B activates transcription from the T-cell receptor beta enhancer. Mixing experiments indicated that AML-1/ETO can efficiently block AML-1B-dependent transcriptional activation, suggesting that the t(8;21) translocation creates a dominant interfering protein.
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23 MeSH Terms
c-jun inhibits insulin control element-mediated transcription by affecting the transactivation potential of the E2A gene products.
Robinson GL, Henderson E, Massari ME, Murre C, Stein R
(1995) Mol Cell Biol 15: 1398-404
MeSH Terms: Adenoviridae, Adenovirus E2 Proteins, Animals, Base Sequence, Cell Line, Cricetinae, DNA Primers, Gene Expression Regulation, Genes, jun, HeLa Cells, Humans, Insulin, Islets of Langerhans, Mice, Molecular Sequence Data, Polymerase Chain Reaction, Proto-Oncogene Proteins c-jun, Transcription, Genetic, Transcriptional Activation, Transfection
Show Abstract · Added December 10, 2013
Pancreatic beta-cell-type-specific transcription of the insulin gene is principally controlled by trans-acting factors which influence insulin control element (ICE)-mediated expression. The ICE activator is composed, in part, of the basic helix-loop-helix proteins E12, E47, and E2-5 encoded by the E2A gene. Previous experiments showed that ICE activation in beta cells was repressed in vivo by the c-jun proto-oncogene (E. Henderson and R. Stein, Mol. Cell. Biol. 14:655-662, 1994). Here we focus on the mechanism by which c-Jun inhibits ICE-mediated activation. c-Jun was shown to specifically repress the transactivation potential of the E2A proteins. Thus, we found that the activity of GAL4:E2A fusion constructs was inhibited by c-Jun. The transrepression capabilities of c-Jun were detected only in pancreatic islet cell lines that contained a functional ICE activator. Repression of GAL4:E2A was mediated by the basic leucine zipper regions of c-Jun, which are also the essential regions of this protein necessary for controlling ICE activator-stimulated expression in vivo. The specific target of c-Jun repression was the transactivation domain (located between amino acids 345 and 408 in E12 and E47) conserved in E12, E47, and E2-5. In contrast, the activation domain unique to the E12 and E47 proteins (located between amino acids 1 and 99) was unresponsive to c-Jun. Our results indicate that c-Jun inhibits insulin gene transcription in beta cells by reducing the transactivation potential of the E2A proteins present in the ICE activator complex.
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20 MeSH Terms
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.
Hoang AT, Lutterbach B, Lewis BC, Yano T, Chou TY, Barrett JF, Raffeld M, Hann SR, Dang CV
(1995) Mol Cell Biol 15: 4031-42
MeSH Terms: Alleles, Amino Acid Sequence, Base Sequence, Burkitt Lymphoma, Cell Transformation, Neoplastic, Cyclins, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Genes, myc, Humans, Models, Genetic, Molecular Sequence Data, Mutation, Nuclear Proteins, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-myc, Retinoblastoma-Like Protein p107, Structure-Activity Relationship, Suppression, Genetic, TATA-Box Binding Protein, Threonine, Transcription Factors, Transcriptional Activation
Show Abstract · Added March 20, 2014
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.
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24 MeSH Terms