Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is accepted that apoptosis is a gene-controlled process of cellular self-destruction. It occurs during physiological regulation and in pathological situations in the life of a cell. In the immune system, several different intracellular and extracellular factors have been associated with the induction of apoptosis, and the final responses depend on the cell system and the acquired signals. In lymphoid cells, dexamethasone-induced apoptosis is associated with c-myc downregulation in cells that remain in G0-G1 until the point of death. Ornithine decarboxylase (ODC), a key enzyme involved in polyamine biosynthesis, is regulated by c-myc, which is a transcriptional activator implicated not only in the control of cell proliferation and differentiation but also in programmed cell death. As dimethylsulphoxide (DMSO) induces apoptosis in the RPMI-8402 human pre-T cell line, the present study analysed the involvement of the c-myc proto-oncogene and polyamine pathway as mediators of apoptosis. Cell growth, programmed cell death, c-myc expression, ODC activity and intracellular polyamine content were detected after DMSO and difluoromethylornithine (DFMO) treatment. DMSO-treated cells exhibit a decrease in ODC activity and polyamine levels associated with cell growth arrest and programmed cell death induction. The expression of c-myc proto-oncogene, as its mRNA or protein, is specifically down-regulated. DFMO, a well defined polyamine biosynthesis inhibitor, completely blocks ODC activity, resulting in growth inhibition but not apoptosis. Moreover, in these samples no evidence of changes of c-myc expression were found. The results obtained suggest that, in RPMI-8402 cells, DMSO provokes a c-myc-dependent decrease of ODC activity followed by a depletion of intracellular polyamine levels, associated with programmed cell death and cell growth arrest.
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PMID:The c-myc gene regulates the polyamine pathway in DMSO-induced apoptosis. 1053 58

Most colorectal cancers have loss-of-function mutations in the adenomatosis polyposis coli (APC) tumor suppressor gene. This leads to the accumulation of nuclear beta-catenin, which, together with the DNA-binding protein TCF-4, functions as a transcriptional activator. The recently defined target genes c-myc, cyclin D1, and matrilysin are responsible for tumor proliferation or malignant progression and explain the oncogenic potential of nuclear beta-catenin. To investigate its role in early colon carcinogenesis, we analyzed the expression of beta-catenin, its target gene c-myc, and the proliferative activity in 88 colorectal adenomas of varying size and grade of dysplasia. The results revealed i) the most significant correlation of nuclear beta-catenin and c-myc expression was not with the grade of dysplasia but with the size of the colon adenoma; ii) perfect correlation of nuclear beta-catenin and c-myc expression; iii) no significant correlation of adenoma size with the proliferative activity; and iv) no significant correlation of proliferative activity and the nuclear expression of beta-catenin and c-myc. These results imply that APC mutations have additional beta-catenin-independent functions; APC mutations alone are not sufficient for nuclear overexpression of beta-catenin; and nuclear beta-catenin has additional important functions for exceeding a threshold tumor size.
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PMID:Expression of nuclear beta-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas. 1070 3

Human MDM2 (hMDM2) inhibits transcriptional activation mediated by wild-type p53 and its tumor-derived mutants. We present evidence to show that hMDM2 interacts with the tumor-derived mutants of p53 and inhibits transcriptional activation of the human c-myc promoter mediated by the tumor-derived mutants of p53 through two domains. These two domains of hMDM2 are able to function independent of each other. Interaction with either of the domains is sufficient for inhibition of mutant p53-mediated transactivation. One of these domains is the same as the wild-type p53 interaction domain of hMDM2, whereas a second domain is situated within amino acid 190 and 276 residues and is specific for mutant p53. hMDM2 does not inhibit transcriptional activation mediated by the transcriptional activator VP16, suggesting that the inhibition is not mediated by inactivation of a general transcription factor. The transactivation and the oligomerization domains of mutant p53 are dispensable for its interaction with hMDM2. Thus, both hMDM2 and p53 recognize each other through unique domains. These observations suggest that forms of hMDM2 incapable of interacting with the wild-type p53, and are often expressed in transformed cells, would inhibit mutant p53-mediated transactivation and antagonize the tumorigenic function of mutant p53. This inhibitory function of hMDM2 may account for infrequent co-occurrence of p53 mutation and hMDM2 overexpression in cancer cells. Our results also suggest distinct mechanisms for wild-type and mutant p53-mediated transcriptional activation.
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PMID:The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants. 1117 71

beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.
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PMID:[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]. 1121 38

Myc is a transcriptional activator whose deregulated expression not only promotes proliferation but also induces or sensitizes cells to apoptosis. Here we demonstrate that c-myc plays a role in triggering apoptosis in CEM T leukaemia cells exposed to progressive medium exhaustion. Indeed starved cells undergo apoptosis in the presence of constitutively elevated c-myc expression and the phorbol ester, phorbol 12-miristate 13-acetate (PMA), which rescues cells from apoptosis, induces complete c-myc down-regulation. We also investigate the hypothesis that ornithine decarboxylase (ODC), a transcriptional target of c-myc, is a down-stream mediator of c-myc driven apoptosis. We demonstrate that PMA induces in starved cells an earlier and larger decrease in ODC expression (mRNA and activity) and intracellular polyamine content, compared to untreated starved cells. Moreover we show that alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzymatic activity, effectively reduces, while exogenous added polyamines enhance apoptosis in starved cells. All these data indicate that ODC and polyamines may act as facilitating factors in triggering apoptosis induced by growth/survival factors withdrawal.
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PMID:Down-modulation of c-myc expression by phorbol ester protects CEM T leukaemia cells from starvation-induced apoptosis: role of ornithine decarboxylase and polyamines. 1159 94

Frizzled-related protein (Frp) is a new family of secreted proteins that contain a region homologous to the extracellular cysteine-rich domain (CRD) of the frizzled family proteins. The role of Frp protein is far from clear. To explore the role of Frp and its relationship to the Wnt-signalling pathway in breast cancer, in situ hybridization and immunohistochemical analyses of Frp, Wnt-1, APC, beta-catenin, and its target genes c-myc and cyclin D1 were conducted in 70 specimens of invasive ductal carcinomas of the human breast. Frp mRNA was down-regulated in 62 and elevated in eight tumour specimens, compared with adjacent normal tissues. In the course of tumour progression, however, Frp mRNA steadily increased in both tumour and the adjacent tissues. Interestingly, the number of cases with axillary lymph node metastasis was significantly lower in the group with elevated Frp than in the group with decreased Frp, suggesting that Frp may contribute as a prognostic factor in invasive breast cancer. Wnt-1, a gene implicated in human breast cancer, was markedly elevated in grade 1 tumours, but declined as tumour grade declined. The level of Wnt-1 was linearly correlated with its downstream target beta-catenin (p<0.05), but was inversely correlated with Frp (p<0.05), suggesting a possible negative regulatory role of Frp with regard to Wnt-1. APC was inversely correlated with beta-catenin (p<0.05). Beta-catenin, a key transcriptional activator responsible for the activation of both c-myc and cyclin D1 in colorectal tumours, was detected at high levels in the plasma membranes of cells in normal tissue. In tumour masses, however, beta-catenin lost its tight association with the membrane and diffused into the cytoplasm. Surprisingly, it clearly did not penetrate the nuclei, despite the fact that both c-myc and cyclin D1 were markedly elevated in all tumour tissues. As revealed in this study, Wnt-1/beta-catenin plays very different roles in the oncogenesis of breast and colon cancers. This first systemic analysis of the Frp and the Wnt-signalling pathway in human breast cancer provides a springboard for further work on the role of Frp in the development of breast cancer.
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PMID:Expression of frizzled-related protein and Wnt-signalling molecules in invasive human breast tumours. 1179 65

Beta-catenin is a transcriptional activator that is regulated by glycogen synthase kinase-3 (GSK-3). GSK-3 is constitutively active in unstimulated cells where it phosphorylates beta-catenin, targeting beta-catenin for rapid degradation. Receptor-induced inhibition of GSK-3 allows beta-catenin to accumulate in the cytoplasm and then translocate to the nucleus where it promotes the transcription of genes such as c-myc and cyclin D1. Wnt hormones, the best known regulators of beta-catenin, inhibit GSK-3 via the Disheveled protein. However, GSK-3 is also inhibited when it is phosphorylated by Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K). We have previously shown that B cell Ag receptor (BCR) signaling leads to activation of PI3K and Akt as well as inhibition of GSK-3. Therefore, we hypothesized that BCR engagement would induce the accumulation of beta-catenin via a PI3K/Akt/GSK-3 pathway. We now show that BCR ligation causes an increase in the level of beta-catenin in the nuclear fraction of B cells as well as an increase in beta-catenin-dependent transcription. Direct inhibition of GSK-3 by LiCl also increased beta-catenin levels in B cells. This suggests that GSK-3 keeps beta-catenin levels low in unstimulated B cells and that BCR-induced inhibition of GSK-3 allows the accumulation of beta-catenin. Surprisingly, we found that the BCR-induced phosphorylation of GSK-3 on its negative regulatory sites, as well as the subsequent up-regulation of beta-catenin, was not mediated by Akt but by the phospholipase C-dependent activation of protein kinase C. Thus, the BCR regulates beta-catenin levels via a phospholipase C/protein kinase C/GSK-3 pathway.
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PMID:The B cell antigen receptor regulates the transcriptional activator beta-catenin via protein kinase C-mediated inhibition of glycogen synthase kinase-3. 1209 78

The expression of the transcriptional activator and tumor suppressor IRF-1 induces multiple effects that counteract the growth of tumor cells in vitro and in vivo. These include the inhibition of cell proliferation, the secretion of interferon-beta (IFN-beta), the induction of apoptosis specifically in certain cell types and the induction of a strong T-cell response. Here, we show that apart from its immune-activating properties, IRF-1 expression leads to a reversion of the tumorigenic phenotype of NIH3T3 cells transformed by different oncogenes. This was analysed in detail in a cell line in which the expression of c-Ha-ras and c-myc is under the control of a doxycycline-regulated promoter allowing to switch between the normal and oncogenic cell status. In the same cells, a beta-estradiol activatable IRF-1 fusion protein is expressed. After IRF-1 activation the oncogene-mediated acceleration of the cell cycle is reverted. Further, a complete IRF-1-mediated reversion of the oncogenic phenotype is observed in soft-agar growth assays. IRF-1 activation induces IFN-beta secretion; however, the observed effects are not mediated by IFN-beta. Inhibition of tumor growth is observed in nude mice as long as IRF-1 is active, indicating that neither B- nor T-cells must become activated for tumor growth suppression.
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PMID:IRF-1 reverts the transformed phenotype of oncogenically transformed cells in vitro and in vivo. 1259 91

A role for histone acetylation, which can alter the accessibility of DNA to transcriptional regulatory proteins and contribute to gene expression, in regulating terminal B cell differentiation was investigated in the mature B lymphoma L10A and mouse splenic B cells. Incubation of the L10A cells with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and butyrate increased expression of Blimp-1, J chain, and mad genes, decreased expression of c-myc and BSAP/Pax-5 genes, increased the expression of surface CD43 and Syndecan-1, and decreased surface IgM. Incubation of splenic B cells with TSA and dextran conjugated anti-IgD Ab increased Blimp-1 gene and Syndecan-1 surface expression. The alteration in gene expression and cell surface markers was consistent with induction of the onset of terminal B cell differentiation. Co-incubation of L10A cells with TSA and cycloheximide (CHX) abrogated the up-regulation of Blimp-1 expression, indicating that TSA-activated Blimp-1 expression required synthesis of a transcriptional activator. In contrast, mad expression was increased in L10A cells cultured with TSA and cycloheximide or cycloheximide alone, suggesting mad expression may occur independent of Blimp-1 expression and is regulated by a labile, HDAC associated transcriptional repressor. The results demonstrate that histone acetylation regulates transcription of genes controlling terminal B cell differentiation.
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PMID:Activation of terminal B cell differentiation by inhibition of histone deacetylation. 1269 18

p38 is associated with a macromolecular tRNA synthetase complex. It has an essential role as a scaffold for the complex, and genetic disruption of p38 in mice causes neonatal lethality. Here we investigated the molecular mechanisms underlying lethality of p38-mutant mice. p38-deficient mice showed defects in lung differentiation and respiratory distress syndrome. p38 was found to interact with FUSE-binding protein (FBP), a transcriptional activator of c-myc. Binding of p38 stimulated ubiquitination and degradation of FBP, leading to downregulation of c-myc, which is required for differentiation of functional alveolar type II cells. Transforming growth factor-beta (TGF-beta) induced p38 expression and promoted its translocation to nuclei for the regulation of FBP and c-myc. Thus, this work identified a new activity of p38 as a mediator of TGF-beta signaling and its functional importance in the control of c-myc during lung differentiation.
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PMID:Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation. 1281 82


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