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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Myc proto-oncogene is a basic helix-loop-helix leucine zipper (b/HLH/LZ) protein that participates in cellular growth and differentiation. The expression of c-Myc mRNA is rapidly induced by nerve growth factor (NGF) and epidermal growth factor (EGF) in PC-12 pheochromocytoma cells. In most cell types, c-Myc forms a sequence-specific DNA binding complex with the stable, constitutively expressed Max. This complex can function as a transcriptional regulator. We show here that the expression of Max mRNA or protein was not detected in PC-12 cells. Nevertheless, treatment of PC-12 cells with NGF and serum caused an increase in the expression of the c-Myc protein and the transcription of a reporter gene linked to the Myc/Max DNA binding site. Transcription from the same reporter gene is stimulated by over-expression of c-Myc. These results suggest that c-Myc protein functions as a transcriptional regulator in PC-12 cells despite the lack of Max protein. Therefore, Myc/Max complexes may not be an absolute requirement for Myc-dependent gene expression.
Mol Cell Neurosci 1994 Jun
PMID:c-Myc does not require max for transcriptional activity in PC-12 cells. 808 25

In the present study we describe the full length cDNA sequence for rabbit transglutaminase type I as well as the sequence for a 2.9-kilobase (kb) promoter fragment of the gene. Transglutaminase type I mRNA expression was inhibited in squamous differentiating epithelia by retinoic acid (RA) in a dose-dependent (EC50 = 1-2 nM) and transcriptional manner. In human epidermal keratinocytes transglutaminase type I mRNA was induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, and this induction could be inhibited by bryostatin 1. In contrast, TPA treatment inhibited the expression of c-myc mRNA. Bryostatin 1 but not RA could prevent this decrease in c-myc mRNA expression, indicating that transglutaminase type I mRNA expression was associated with differentiation and not growth arrest. An SP1 element was found within 50 base pairs 5' of the transcription initiation site. A TATA-like element (CATAAAC) was found but was not capable of activating transcription. In addition, putative response elements for C-MYC, Ker1/AP2, 2 AP1 sites, a CK-8-mer, and an AP2 site were present in the 2.9-kb fragment. Transfection of RbTE cells with the 2.9-kb fragment ligated to a promoterless luciferase vector resulted in 2.2-fold more luciferase expression in differentiated vs. undifferentiated cells. Furthermore, luciferase activity was induced 7.4-fold in human epidermal keratinocytes induced to differentiate with TPA. TPA-induced luciferase activity was inhibited by both bryostatin 1 and RA. No known RA response elements were identified in the promoter.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1993 Mar
PMID:Regulation of transglutaminase type I expression in squamous differentiating rabbit tracheal epithelial cells and human epidermal keratinocytes: effects of retinoic acid and phorbol esters. 809 65

The ability of a transcription factor to function in vivo must be determined in part by its ability to bind to its recognition site in chromatin. We have used Max and derivatives of c-Myc to characterize the effect of changes of dimerization partner on binding to nucleosomal DNA templates. We find that homo- and heterodimeric complexes of these proteins bind to the CACGTG sequence in free DNA with similar affinities. Although Max homodimers bind to nucleosomes, truncated c-Myc homodimers do not. Surprisingly, modifying the c-Myc dimerization interface or changing its dimerization partner to Max enables nucleosomal DNA binding. Thus, changes in dimer structure or dimerization efficiency can have significant effects on nucleosome binding that are not predicted from their affinity for free DNA. We conclude that domains other than the basic region per se influence the ability of a transcription factor to bind to nucleosomal DNA and that changes of dimerization partner can directly affect the ability of a factor to occupy nucleosomal binding sites.
Mol Cell Biol 1994 Jun
PMID:Differential binding of c-Myc and Max to nucleosomal DNA. 819 48

Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested that high protein levels of cyclin D1 are not always produced when cyclin D1 mRNA is overexpressed in transfected cells, suggesting that posttranscriptional events may be important in cyclin D1 regulation. The mRNA cap-binding protein (eukaryotic initiation factor 4E [eIF-4E]) is a potential regulatory of several posttranscriptional events, and it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as a potential regulator of cyclin D1. Overexpression of cyclin D1 mRNA in NIH 3T3 cells did not increase cyclin D1 protein. In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells. This increase was specific to cyclin D1 in comparison with the retinoblastoma gene product, c-Myc, actin, and eukaryotic initiation factor 2 alpha. We also examined cyclin D1 protein in cells expressing an estrogen receptor-Myc fusion protein because we previously found that eIF-4E increases after induction of c-myc function. In these cells, increased levels of eIF-4E protein were closely followed by increases in levels of cyclin D1 protein, but the level of cyclin D1 mRNA was not increased. We conclude that increases in cyclin D1 levels may result from increased expression of eIF-4E, and this regulation may be one determinant of cyclin D1 levels in the cell.
Mol Cell Biol 1993 Dec
PMID:Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. 824 56

The c-myc proto-oncogene encodes nuclear phosphoproteins that bind DNA in a sequence-specific fashion and appear to function as transcriptional activators. Here we demonstrate that a 40-kDa nuclear protein coimmunoprecipitated with c-Myc specifically when nuclear proteins, extracted from nuclei of exponentially growing murine B-lymphoma WEHI 231 cells by using procedures for preparation of trans-acting factors, were reacted with anti-c-Myc antibodies made against different regions of the c-Myc protein. In contrast, preparation of nuclear lysates under denaturing conditions significantly reduced this coprecipitation. Upon incubation of WEHI 231 cells with the reversible chemical cross-linking agent dithiobis(succinimidyl propionate), the 40-kDa protein could be cross-linked to c-Myc protein intracellularly. Identification of the 40-kDa protein as the TATA-binding protein (TBP) of the TFIID transcription initiation complex was made by comigration and V-8 protease mapping, which yielded identical peptide fragments upon digestion of the 40-kDa protein and material immunoprecipitated with an anti-TBP specific antibody. Furthermore, in vitro-translated TBP bound to the amino-terminal portion of c-Myc. Column chromatography of cross-linked nuclear proteins showed TBP to be in a large-molecular-weight complex with c-Myc, consistent with a transcription initiation complex. These results indicate that intracellularly, c-Myc interacts with TBP, suggesting a mechanism of interaction of this oncoprotein with the basal transcription machinery.
Mol Cell Biol 1994 Feb
PMID:Intracellular association of the protein product of the c-myc oncogene with the TATA-binding protein. 828 95

Using an in vitro binding-site selection assay, we have demonstrated that c-Myc-Max complexes bind not only to canonical CACGTG or CATGTG motifs that are flanked by variable sequences but also to noncanonical sites that consist of an internal CG or TG dinucleotide in the context of particular variations in the CA--TG consensus. None of the selected sites contain an internal TA dinucleotide, suggesting that Myc proteins necessarily bind asymmetrically in the context of a CAT half-site. The noncanonical sites can all be bound by proteins of the Myc-Max family but not necessarily by the related CACGTG- and CATGTG-binding proteins USF and TFE3. Substitution of an arginine that is conserved in these proteins into MyoD (MyoD-R) changes its binding specificity so that it recognizes CACGTG instead of the MyoD cognate sequence (CAGCTG). However, like USF and TFE3, MyoD-R does not bind to all of the noncanonical c-Myc-Max sites. Although this R substitution changes the internal dinucleotide specificity of MyoD, it does not significantly alter its wild-type binding sequence preferences at positions outside of the CA--TG motif, suggesting that it does not dramatically change other important amino acid-DNA contacts; this observation has important implications for models of basic-helix-loop-helix protein-DNA binding.
Mol Cell Biol 1993 Sep
PMID:Binding of myc proteins to canonical and noncanonical DNA sequences. 839

The c-Myc oncoprotein, which is required for cellular proliferation, resembles in its structure a growing number of transcription factors. However, the mechanism of its action in vivo is not yet clear. The discovery of the specific cognate DNA-binding site for Myc and its specific heterodimerization partner, Max, enabled the use of direct experiments to elucidate how Myc functions in vivo and how this function is modulated by Max. Here we demonstrate that exogenously expressed Myc is capable of activating transcription in vivo through its specific DNA-binding site. Moreover, transcriptional activation by Myc is dependent on the basic region, the integrity of the helix-loop-helix and leucine zipper dimerization motifs located in the carboxy-terminal portion of the protein, and the regions in the amino terminus conserved among Myc family proteins. In contrast to Myc, exogenously expressed Max elicited transcriptional repression and blocked transcriptional activation by Myc through the same DNA-binding site. Our results suggest a functional antagonism between Myc and Max which is mediated by their relative levels in the cells. A model for the activity of Myc and Max in vivo is presented.
Mol Cell Biol 1993 Jan
PMID:Sequence-specific transcriptional activation by Myc and repression by Max. 841 37

B-myc is a recently described myc gene whose product has not been functionally characterized. The predicted product of B-myc is a 168-amino-acid protein with extensive homology to the c-Myc amino-terminal region, previously shown to contain a transcriptional activation domain. We hypothesized that B-Myc might also function in transcriptional regulation, although its role in regulating gene expression is predicted to be unique, because B-Myc lacks the specific DNA-binding motif found in other Myc proteins. To determine whether B-Myc could interact with the transcriptional machinery, we studied the transcriptional activation properties of a chimeric protein containing B-Myc sequences fused to the DNA-binding domain of the yeast transcriptional activator GAL4 (GAL4-B-Myc). We found that GAL4-B-Myc strongly activated expression of a GAL4-regulated reporter gene in mammalian cells. In addition, full-length B-Myc was able to inhibit or squelch reporter gene activation by a GAL4 chimeric protein containing the c-Myc transcriptional activation domain. We also observed that B-Myc dramatically inhibited the neoplastic cotransforming activity of c-Myc and activated Ras in rat embryo cells. Because B-Myc inhibits both neoplastic transformation and transcriptional activation by c-Myc, we suggest that the transforming activity of c-Myc is related to its ability to regulate transcription. Whether B-Myc functions biologically to squelch transcription and/or to regulate transcription through a specific DNA-binding protein remains unestablished.
Mol Cell Biol 1993 Feb
PMID:B-myc inhibits neoplastic transformation and transcriptional activation by c-myc. 842 80

The product of the c-myc proto-oncogene is an important positive regulator of cell growth and proliferation. Recently, c-Myc has also been demonstrated to be a potent inducer of apoptosis when expressed in the absence of serum or growth factors. To further examine Myc-induced apoptosis, we coexpressed the proto-oncogene bcl2, which has been shown to block apoptosis in other systems, with c-myc in serum-deprived Rat 1a fibroblasts. Here we report that ectopic expression of bcl2 specifically blocks apoptosis induced by constitutive c-myc expression. Constitutive c-myc expression in serum-deprived Rat 1a cells caused a > 15-fold increase in the number of dead cells, accompanied by DNA fragmentation. However, coexpression of bcl2 with c-myc in these cells led to a 10-fold increase in the number of live cells and a significant decrease in DNA fragmentation. Thus, Bcl-2 effectively inhibits Myc-induced apoptosis in serum-deprived Rat 1a fibroblasts without blocking entry into the cell cycle. These results imply that apoptosis serves as a protective mechanism to prevent tumorigenicity elicited by deregulated Myc expression. This protective mechanism is abrogated, however, by Bcl-2 and therefore may explain the synergism between Myc and Bcl-2 observed in certain tumor cells.
Mol Cell Biol 1993 Apr
PMID:Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. 845 20

To gain insight into the role of Myc family oncoproteins and their associated protein Max in vertebrate growth and development, we sought to identify homologs in the zebra fish (Brachydanio rerio). A combination of a polymerase chain reaction-based cloning strategy and low-stringency hybridization screening allowed for the isolation of zebra fish c-, N-, and L-myc and max genes; subsequent structural characterization showed a high degree of conservation in regions that encode motifs of known functional significance. On the functional level, zebra fish Max, like its mammalian counterpart, served to suppress the transformation activity of mouse c-Myc in rat embryo fibroblasts. In addition, the zebra fish c-myc gene proved capable of cooperating with an activated H-ras to effect the malignant transformation of mammalian cells, albeit with diminished potency compared with mouse c-myc. With respect to their roles in normal developing tissues, the differential temporal and spatial patterns of steady-state mRNA expression observed for each zebra fish myc family member suggest unique functions for L-myc in early embryogenesis, for N-myc in establishment and growth of early organ systems, and for c-myc in increasingly differentiated tissues. Furthermore, significant alterations in the steady-state expression of zebra fish myc family genes concomitant with relatively constant max expression support the emerging model of regulation of Myc function in cellular growth and differentiation.
Mol Cell Biol 1993 May
PMID:Zebra fish myc family and max genes: differential expression and oncogenic activity throughout vertebrate evolution. 847 40


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