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

Previous studies showed that the core promoter of the mouse cAMP-dependent protein kinase regulatory subunit type II beta (RII beta) gene was composed of two functional elements. One element was GC rich and bound the Sp1 transcription factor. The second element contained a helix-loop-helix (HLH)-motif. Each element conferred transcriptional activity when inserted upstream of a reporter gene, chloramphenicol acetyltransferase and transfected into mouse NB2a neuroblastoma cells and Chinese hamster ovary (CHO) cells. The core promoter was further characterized by mutational analysis using electrophoretic mobility shift assays and by transfection into CHO and NB2a cells. Electrophoretic mobility shift assays showed that the HLH-consensus motif, CACGTG, present in the RII beta gene bound nuclear factors present in NB2a and CHO cells. Mutations in the HLH-core motif decreased the binding of these factors and reduced the transcriptional activity of constructs containing the chloramphenicol acetyltransferase reporter when transfected into these cells. The results showed that the central nucleotides as well as the adjacent bases were important for the interaction with the nuclear binding factors. UV cross-linking, Southwestern blot analysis, and interference of the mobility shift patterns by specific antisera directed against USF and c-Myc indicated that both of these transcription factors were forming complexes with the HLH-consensus motif. The results suggest that RII beta transcription may be regulated, in part, by USF and c-Myc in NB2a and CHO cells.
Mol Endocrinol 1994 Sep
PMID:Association of USF and c-Myc with a helix-loop-helix-consensus motif in the core promoter of the murine type II beta regulatory subunit gene of cyclic adenosine 3', 5'-monophosphate-dependent protein kinase. 783 49

Cell transformation by nuclear oncogenes such as c-myc presumably involves the transcriptional activation of a set of target genes that participate in the control of cell division. The function of a small evolutionarily conserved domain of the c-myc gene encompassing amino acids 129 to 145 was analyzed to explore the relationship between cell transformation and transcriptional activation. Deletion of this domain inactivated the c-myc oncogene for cell transformation while retaining the ability to activate transcription of either myc consensus binding sites or a GAL4-dependent promoter when the c-myc N-terminus was fused to the GAL4 DNA-binding domain. Point mutations that altered a conserved tryptophan (amino acid 136) within this domain had similar effects. Expression of the wt c-Myc N terminus (amino acids 1 to 262) as a GAL4 fusion was a dominant inhibitor of cell transformation by the c-myc oncogene, and this same domain also inhibited transformation by the adenovirus E1A gene. Surprisingly, deletion of amino acids 129 to 145 eliminated the dominant negative activity of GAL4-Myc on both c-myc and E1A transformation. Expression of the GAL4-Myc protein in Cos cells led to the formation of a specific complex between the Myc N terminus and a nuclear factor, and this complex was absent with the dl129-145 mutant. These results suggest that an essential domain of the c-Myc protein interacts with a specific nuclear factor that is also required for E1A transformation.
Mol Cell Biol 1995 Mar
PMID:An essential domain of the c-myc protein interacts with a nuclear factor that is also required for E1A-mediated transformation. 786 46

Activation of the c-myc proto-oncogene by chromosomal translocation or proviral insertion frequently results in the separation of the c-myc coding region from its normal regulatory elements. Such rearrangements are often accompanied by loss or mutation of c-myc exon 1 sequences. These genetic alterations do not affect synthesis of the major c-myc protein, p64, which is initiated from the first AUG codon in exon 2. However they can result in mutation or loss of the CUG codon located in exon 1 that normally serves as an alternative translational initiation codon for synthesis of an N-terminally extended form of c-Myc (p67). It has been hypothesized that p67 is a functionally distinct form of c-Myc whose specific loss during c-myc rearrangements confers a selective growth advantage. Here we describe experiments designed to test the functional properties of the two c-Myc protein forms. We introduced mutations within the translational initiation codons of a normal human c-myc cDNA that alter the pattern of Myc protein synthesis (p64 vs. p67). The functions of each of these proteins were experimentally addressed using co-transformation and transcriptional activation assays. Both the p64 and p67 c-Myc proteins were independently able to collaborate with bcr-abl in the transformation of Rat-1 fibroblasts. In addition, both the exon 1- and exon 2-initiated forms of the c-Myc protein stimulated transcription of a Myc/Max-responsive reporter construct to a similar level. Given the apparent absence of functional differences between p64 and p67, we conclude that the basis for c-Myc oncogenic activation lies primarily in the overall deregulation of its expression and not in alterations in the protein. The existence of the CUG translational initiator may reflect a mechanism for the continued synthesis of c-Myc protein under conditions where AUG initiation is inhibited.
Mol Biol Cell 1994 May
PMID:Functional analysis of the AUG- and CUG-initiated forms of the c-Myc protein. 791 40

We investigated signal transduction pathways involved in c-myc activation, using rat hepatocytes in primary culture. c-Myc mRNA was constantly expressed in the cultured hepatocytes regardless of the conditions present. When the expression was examined in the presence of various agents modulating intracellular signals, isoflavonoids (genistein, psi-tectorigenin, and orobol) significantly decreased c-myc mRNA levels, in a dose dependent manner. However, genistein did not decrease Li+ induced inositol phosphate accumulation using [3H]inositol-labeled cultured hepatocytes. In addition, we have shown that these isoflavonoids increase cytoplasmic free Ca2+, when measured using aequorin-loaded hepatocytes. In light of these observations, the persistent basal level of c-myc expression seems to be maintained by mechanisms other than phosphatidylinositol turnover.
Biochem Mol Biol Int 1994 Jun
PMID:Signaling pathway other than phosphatidylinositol turnover is responsible for constant expression of c-myc gene in primary cultures of rat hepatocytes. 795 Oct 61

Elevated levels of mutant forms of the p53 tumor suppressor are a hallmark of many transformed cells. Multiple mechanisms such as increased stability of the protein and increased transcription of the gene can account for elevated p53 expression. Recent findings indicate that c-Myc/Max heterodimers can bind to an essential CA(C/T)GTG-containing site in the p53 promoter and elevate its expression. We have addressed the possibility that elevated mutant p53 expression is due to deregulated c-Myc expression. Here we demonstrate that the human p53 promoter is transactivated by high c-Myc expression and repressed by high Max expression. In examining the relative levels of c-Myc and p53 in human Burkitt's lymphomas and other B-lymphoid lines, we found that there is a correlation between the levels of c-Myc protein and p53 mRNA expression. In particular, cells that express very low levels of c-Myc protein also express low levels of p53 mRNA, while cells that express high levels of c-Myc tend to express high levels of p53 mRNA. To determine whether the p53 gene can be a target for c-Myc in vivo, we assayed the effects of antisense c-myc RNA on the levels of endogenous p53 mRNA. The results indicate that the presence of antisense c-myc RNA leads to a reduction in the levels of c-Myc protein, p53 mRNA, and expression from the p53 promoter. Taken together, our findings support a direct role for c-Myc in elevating expression of the mutant p53 gene in some tumors.
Mol Cell Biol 1994 Dec
PMID:Transactivation of the human p53 tumor suppressor gene by c-Myc/Max contributes to elevated mutant p53 expression in some tumors. 796 21

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.
Mol Cell Biol 1994 Aug
PMID:Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-Myc protein is regulated by mitogens and in mitosis. 803 27

Glucocorticoids inhibit proliferation of L929 fibroblastic cells in culture. Inhibition of proliferation is reversible and is not associated with changes in the plating efficiency of the cells. Flow cytometric analysis indicates that glucocorticoid-treated cells exhibit a decrease in the percentage of cells with DNA content > 2 N. Thymidine kinase expression is inhibited as cells with 2 N DNA content accumulate. These observations indicate that glucocorticoids arrest proliferation of L929 cells in the G1 phase of the cell cycle. The abundance of c-Myc mRNA does not decrease in glucocorticoid-treated cells, and c-Myc protein content in dexamethasone-treated cells is approximately the same as that detected in mid-log phase cells. Nuclear run-on transcription of c-Myc is not inhibited by glucocorticoids. These observations indicate that glucocorticoid regulation of fibroblastic cell proliferation does not involve inhibition of c-Myc transcription. Although regulation of c-Myc expression is central to the mechanism whereby glucocorticoids regulate proliferation of lymphoid cells, it is clear that different mechanisms must be involved in glucocorticoid regulation of fibroblastic cell proliferation.
J Steroid Biochem Mol Biol 1994 Aug
PMID:Expression of c-Myc in glucocorticoid-treated fibroblastic cells. 804 39

The phosphoprotein c-Myc has the potential to kill cells by apoptosis. To investigate whether c-Myc is involved in tumor necrosis factor alpha (TNF-alpha)-mediated cell killing, we have examined two HeLa cell lines (D98 and H21) which show dramatic differences in their susceptibilities to TNF-alpha cytotoxicity. Northern (RNA) blot analyses showed that there were no significant differences between these cell lines in basal or TNF-alpha-induced mRNA expression for a variety of proteins, including manganous superoxide dismutase, A20 zinc finger protein, plasminogen activator inhibitor type 2, and hsp70, all of which are known to influence the susceptibility of certain cells to TNF-alpha killing. On the other hand, there was a dramatic increase in c-Myc mRNA expression in TNF-alpha-sensitive D98 cells, but not in TNF-alpha-resistant H21 cells, which was only observed when the cells were treated with cycloheximide. Western blot (immunoblot) analyses revealed that even in the absence of TNF-alpha or cycloheximide, c-Myc was detectable only in nuclear extracts of TNF-alpha-sensitive D98 cells, implying a role for preexisting c-Myc in TNF-alpha killing. In support of this interpretation, a c-myc antisense oligonucleotide specifically inhibited the TNF-alpha killing of D98 cells, provided that the oligonucleotide was added 6 h prior to TNF-alpha treatment. Either dexamethasone treatment or transient expression of c-myc antisense cDNA fragments decreased nuclear c-Myc in D98 cells and rendered the cells more resistant to TNF-alpha cytotoxicity. Nuclear c-Myc was also detectable in a TNF-alpha-sensitive human HT-1080 fibrosarcoma cell line, but it was undetectable in a derivative of HT-1080 (SS-HT-1080) known to be resistant to TNF-alpha killing because of overexpression of plasminogen activator inhibitor type 2. HT-1080 cells transfected with antisense c-myc cDNA had significantly less nuclear c-Myc and were resistant to TNF-alpha cytotoxicity. Together, these data indicate that a nuclear transcription factor, c-Myc, plays an important role in sensitizing two different tumor cell types to TNF-alpha cytotoxicity.
Mol Cell Biol 1994 Sep
PMID:Nuclear c-Myc plays an important role in the cytotoxicity of tumor necrosis factor alpha in tumor cells. 806 3

Expression of c-myc with constitutively active mutants of the ras gene results in the cooperative transformation of primary fibroblasts, although the precise mechanism by which these genes cooperate is unknown. Since c-Myc has been shown to function as a transcriptional activator, we have examined the ability of c-Myc and activated Ras (H-RasV-12) to cooperatively induce the promoter activity of cdc2, a gene which is critical for cell cycle progression. Microinjection of expression constructs encoding H-RasV-12 and c-Myc along with a cdc2 promoter-luciferase reporter plasmid into quiescent cells led to an increase in cdc2 promoter activity approximately 30 h after injection, a period which coincides with the S-to-G2/M transition in these cells. Expression of H-RasV-12 alone weakly activated the cdc2 promoter, while expression of c-Myc alone had no effect. Mutants of c-Myc lacking either the leucine zipper dimerization domain or the phosphoacceptor site Ser-62 could not cooperate with H-RasV-12 to induce the cdc2 promoter. These mutants also lacked the ability to cooperate with H-RasV-12 to stimulate DNA synthesis. Deletion analysis identified a distinct region of the cdc2 promoter which was required for c-Myc responsiveness. Taken together, these observations suggest a mechanistic link between the molecular activities of c-Myc and Ras and induction of the cell cycle regulator Cdc2.
Mol Cell Biol 1994 Sep
PMID:c-Myc cooperates with activated Ras to induce the cdc2 promoter. 806 6

c-Myc plays a central role in the regulation of cell cycle progression, differentiation, and apoptosis. However, the proteins which mediate c-Myc function(s) remain to be determined. Enforced c-myc expression rapidly induces apoptosis in interleukin-3 (IL-3)-dependent 32D.3 murine myeloid cells following IL-3 withdrawal, and this is associated with the constitutive, growth factor-independent expression of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis. Here we have examined the role of ODC in c-Myc-induced apoptosis. Enforced expression of ODC, like c-myc, is sufficient to induce accelerated death following IL-3 withdrawal. ODC induced cell death in a dose-dependent fashion, and alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzyme activity, effectively blocked ODC-induced cell death. ODC-induced cell death was due to the induction of apoptosis. We also demonstrate that ODC is a mediator of c-Myc-induced apoptosis. 32D.3-derived c-myc clones have augmented levels of ODC enzyme activity, and their rates of death were also a function of their ODC enzyme levels. Importantly, the rates of death of c-myc clones were inhibited by treatment with DFMO. These findings demonstrate that ODC is an important mediator of c-Myc-induced apoptosis and suggest that ODC mediates other c-Myc functions.
Mol Cell Biol 1994 Sep
PMID:Ornithine decarboxylase is a mediator of c-Myc-induced apoptosis. 806 8


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