Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we analyzed the effect of the suppressor proto-oncogene p53 on transcription from the P2 promoter of the murine c-myc gene. c-myc promoter constructs were coupled to the chloramphenicol acetyl-transferase (CAT) gene and were transiently transfected into a human glial cell along with plasmids overexpressing wild-type or mutant p53. It was found that significant repression of c-myc transcription took place following cotransfection with wild-type but not mutant p53. However wild-type p53 did not suppress transcription from the SV40 early promoter or from the MHC promoter. Promoter-CAT constructs containing only the ME1a2 or E2F elements, from the P2 promoter, were repressed by p53, indicating that p53 may exert its effect at these two sites within the P2 promoter. Finally, when the SV40 T antigen and wild-type p53 were expressed together in glial cells the repressive effect of p53 was abolished.
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PMID:Wild-type murine p53 represses transcription from the murine c-myc promoter in a human glial cell line. 140 Jun 26

Mouse 10T1/2 cells were transfected with combinations of T24 H-ras, human c-myc and the proline 193 mutant form of p53. The three-gene ras/myc/p53 combination was significantly more efficient than single genes or double gene combinations in inducing transformed foci in vitro. An analysis of cell lines isolated after transfections with ras, ras/myc, ras/p53 and ras/myc/p53 indicated that the last combination contained significantly higher levels of ras protein than the other combinations, produced tumors in syngeneic mice with a shorter latency period, and exhibited an increased ability to form lung tumors in an in vivo experimental metastasis assay. Synergistic interactions between ras, myc and mutant p53 genes were observed in focus formation and metastasis assays, suggesting that the action of the three oncogenes in malignant transformation occurs along separate but interactive pathways. These results support a working model of oncogene cooperativity in which alterations in myc and p53 permit elevated expression of ras, which is important in a mechanism affecting both cellular transformation in vitro and tumor dissemination in vivo.
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PMID:Evidence for synergistic interactions between ras, myc and a mutant form of p53 in cellular transformation and tumor dissemination. 162 May 51

An invariant genetic lesion in mouse plasmacytomas is deregulated expression of c-myc as a consequence of chromosomal translocation. However, retroviral and transgenic studies suggest that additional genetic lesions may contribute to the genesis of plasmacytomas. The p53 tumor suppressor gene is a likely contributor to this genetic lesion, since there is a high incidence of p53 mutation in Burkitt's lymphomas and B-ALL (L3), both of which contain translocations involving c-myc analogous to those in plasmacytomas. In addition, p53 has been shown to be a transcriptional modulator of c-myc expression. In a survey of 27 mouse plasmacytomas by single-strand conformation polymorphism, we identified a single mutation (3.7% incidence), suggesting that p53 lesions are not frequent contributors to plasmacytomagenesis. A similar study of macrophage-monocyte tumors generated by a c-myc-containing retrovirus also indicates a lack of p53 involvement in deregulated c-myc expression. These results suggest that the specific maturation stage of transformed B-lymphocytes, independent of c-myc deregulation, may be the critical factor which determines the involvement of mutant p53.
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PMID:Infrequent p53 mutation in mouse tumors with deregulated myc. 173 33

Transforming growth factor beta 1 (TGF beta 1) is the prototype of a large family of polypeptides involved in growth control, extracellular matrix production, and development. The TGF beta s have marked stimulatory effects on connective tissue formation. They are chemotactic for fibroblasts, indirect mitogens for certain mesenchymal cells and stimulators of extracellular matrix deposition. The TGF beta s are also potent inhibitors of proliferation of most cell types in culture, and in vivo studies have indicated that the predominant effect of TGF beta 1 on cell proliferation is inhibition. We have investigated the mechanism of TGF beta 1 inhibition of skin keratinocyte growth. Earlier studies demonstrated that TGF beta 1 inhibition of keratinocyte proliferation involves suppression of c-myc transcription, and indirect evidence suggested that the product of the retinoblastoma tumor susceptibility gene, pRB, may be involved in this process. More recently, we have shown that transient expression of pRB in skin keratinocytes can repress human c-myc promoter/CAT transcription as effectively as TGF beta 1. The same c-myc promoter region, termed the TGF beta control element (TCE), was required for regulation by both TGF beta 1 and pRB. Oligonucleotides containing the TCE bound to several nuclear factors in mobility shift assays and a cellular protein of approximately 106 kD in Southwestern assays. Binding of these factors could be demonstrated in cells with or without normal pRB, and the binding of some factors was rapidly inhibited by TGF beta 1 treatment of TGF beta-sensitive but not TGF beta-insensitive cells. These data indicate that pRB can function to inhibit c-myc transcription and suggest the involvement of cellular factor(s) in addition to pRB in the TGF beta 1 pathway for suppression of c-myc transcription. Studies with other cell types have shown that another tumor suppressor gene, p53, can also regulate transcription of c-myc in transient assays. Whereas wild type p53 markedly suppressed transcription, four different mutant p53 clones caused transactivation. The data support the hypothesis that pRB and p53 can both cause growth inhibition by blocking the expression of the protooncogene, c-myc, and indicate that tumor suppressor genes may function in the response pathway for diffusible negative growth regulators such as TGF beta.
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PMID:TGF beta regulation of epithelial cell proliferation: role of tumor suppressor genes. 184 40

This study examined the effect of transforming growth factor beta-1 (TGF-beta 1) on c-myc, RB1, junB and p53 expression together with pRb phosphorylation, in carcinoma-derived and normal human oral keratinocytes with a range of inhibitory responses to this ligand. Amplification of c-myc was observed in eight of eight tumour-derived cell lines and resulted in corresponding mRNA expression. The down-regulation of c-myc expression by TGF-beta 1 predominantly reflected growth inhibition by TGF-beta 1, but in two of eight tumour-derived cell lines which were partially responsive to TGF-beta 1 c-myc expression was unaltered by this ligand. While RB1 mRNA levels were unaltered by TGF-beta 1, the ligand caused the accumulation of the underphosphorylated form of the Rb protein in all cells irrespective of TGF-beta 1-induced growth arrest. junB expression was up-regulated by TGF-beta 1 in cells with a range of growth inhibitory responses. All cells contained mutant p53. TGF-beta 1 did not affect p53 mRNA expression in both tumour-derived and normal keratinocytes and there was no alteration in p53 protein levels in keratinocytes expressing stable p53 protein following TGF-beta 1 treatment. The data indicate that TGF-beta-induced growth control can exist independently of the presence of mutant p53 and the control of Rb phosphorylation and c-myc down-regulation. It may be that TGF-beta growth inhibition occurs via multiple mechanisms and that the loss of one pathway during tumour progression does not necessarily result in the abrogation of TGF-beta-induced growth control.
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PMID:Effects of transforming growth factor beta-1 on growth-regulatory genes in tumour-derived human oral keratinocytes. 754 41

The p53 tumor suppressor gene product, and the bcr-abl, bcl-2, and c-myc gene products all appear to influence the susceptibility of cells to apoptosis. In addition to the role p53 protein plays in mediating a cell cycle arrest in G1 following DNA damage, p53 also performs functions critical for removal of damaged cells by initiating apoptosis in certain physiological situations. Cells which express deregulated c-myc are sensitized to apoptosis following various growth suppressing stimuli and these observations have provided new insights into how apoptosis-suppressing genes such as mutant p53, bcl-2 and bcr-abl may cooperate during transformation and how they might influence the sensitivity of cells to radiation and chemotherapy.
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PMID:Induction of apoptosis by tumor suppressor genes and oncogenes. 754 37

Myeloid leukemic M1 cells that do not express p53 and transfected M1 clones that constitutively express the [Val135]p53 mutant or deregulated c-myc or coexpressing both genes grew autonomously in culture with a similar growth rate and cloning efficiency. Expression of deregulated c-myc in M1 leukemic cells enhanced susceptibility to induction of apoptotic cell death and resulted in a reduced leukemogenicity when injected into isologous mice. Expression of the [Val135]p53 mutant did not change cell susceptibility to induction of apoptosis or leukemogenicity, but expression of this mutant p53 suppressed the effects of deregulated c-myc on these properties. The results indicate that the [Val135]p53 mutant can show a gain of function for susceptibility to apoptosis and leukemogenicity in leukemic cells with deregulated c-myc and, thus, enhance tumor development.
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PMID:A mutant p53 antagonizes the deregulated c-myc-mediated enhancement of apoptosis and decrease in leukemogenicity. 756 95

Apoptosis of vascular smooth muscle cells has recently been described in culture and also in remodeling of the artery after birth. However, the genes that regulate apoptosis in smooth muscle cells are mostly unknown. We studied the regulation of apoptosis in rat smooth muscle cells stably infected with retrovirus constructs containing c-myc, adenovirus E1A, bcl-2, and a temperature-sensitive mutant of the tumor suppressor gene p53. Apoptosis was verified by electron microscopy and quantified by time-lapse videomicroscopy. Death was induced by c-myc and E1A when cells were deprived of serum survival factors, bcl-2 suppressed apoptosis of cells infected with c-myc and E1A and also normal smooth muscle cells. Overexpression of wild-type p53 induced apoptosis of cells infected with E1A and c-myc but not normal cells. In contrast, expression of mutant p53, which blocks wild-type p53 function, suppressed apoptosis of cells infected with E1A or c-myc but not normal cells. Both adenovirus E1A and c-myc increased the expression of endogenous p53 protein but not p53 mRNA. Although bcl-2 suppressed apoptosis induced by E1A and c-myc, upregulation of p53 protein induced by these agents was unaffected. We conclude that apoptosis of vascular smooth muscle cells is regulated by p53-dependent and -independent pathways. Death induced by c-myc and E1A is mediated by, and dependent on, p53. However, the suppression of apoptosis by bcl-2 is not mediated by changes in p53 expression, and the low level of apoptosis seen in normal VSMCs upon removal of survival factors is independent of p53.
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PMID:Apoptosis of rat vascular smooth muscle cells is regulated by p53-dependent and -independent pathways. 761 13

In this study, we examined the expression of c-fos, c-myc, mutant c-Ha-ras and mutant p53 proteins in three normal human melanocyte cell lines and the following 12 melanoma cell lines: M5, Mewo, A375, Bro, Mel 2a, O-Mel II, IgR 39, SkMel-13, -19, -28 Mel-57 and NKI-4, using an immunohistochemical assay (APAAP). An effort was made to correlate oncogene expression with growth parameters, differentiation antigens (HMB-45, vla-2, k.1.2.58, HLA-DR, HLA-I), and pigmentation. All melanocyte cell lines were negative for the oncogenes examined, whereas six of the melanoma cell lines were found also positive (three for c-fos, two for c-myc, one for c-Ha-ras, and four for p53). Three melanoma cell lines expressed one oncogene and three the combination c-fos/p53. These three melanoma cell lines were positive for the "late" tumor progression marker A. 1.43 (vla-2 adhesion molecule) and negative for the differentiation marker k. 1. 2. 58. Positivity for A. 1. 43 combined with negative staining for k. 1. 2. 58 was found in six out of the 12 cell lines. The observed oncogene expression correlated neither with growth parameters nor melanin content. The present findings revealed a coexpression of mutant p53 and c-fos proteins being associated with a highly malignant phenotype in melanoma cell lines. Further studies are necessary to clarify the significance of the above findings.
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PMID:P53 mutation and c-fos overexpression are associated with detection of the antigen VLA-2 in human melanoma cell lines. 788 7

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.
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PMID:Transactivation of the human p53 tumor suppressor gene by c-Myc/Max contributes to elevated mutant p53 expression in some tumors. 796 21


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