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)

Interferon regulatory factor-1 (IRF-1) acts as a transcriptional activator in the interferon system and as a tumor suppressor. The loss of functional IRF-1 has been observed in a significant number of patients with myelodysplastic syndrome (MDS) and leukemia, suggesting a potentially critical role of IRF-1 in human oncostasis. Here we report an alternative mechanism by which IRF-1 may be inactivated. We purified an IRF-1 association molecule which was revealed to be identical to a nuclear factor nucleophosmin (NPM)/B23/numatrin. Functional analysis showed that NPM inhibited the DNA-binding and transcriptional activity of IRF-1. Moreover, NPM was overexpressed in several clinical leukemia samples and human-derived leukemia cell lines. Finally, overexpression of NPM in NIH3T3 cells resulted in malignant transformation. These results suggest the possible involvement of NPM in inactivating IRF-1-dependent anti-oncogenic surveillance in human cancer development.
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PMID:Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity. 931 94

Chromosomal translocations resulting in chimaeric transcription factors underlie specific malignancies, but few authentic target genes regulated by these fusion proteins have been identified. Desmoplastic small round-cell tumour (DSRT) is a multiphenotypic primitive tumour characterized by massive reactive fibrosis surrounding nests of tumour cells. The t(11;22)(p13;q12) chromosomal translocation that defines DSRT produces a chimaeric protein containing the potential transactivation domain of the Ewing-sarcoma protein (EWS) fused to zinc fingers 2-4 of the Wilms tumour suppressor and transcriptional repressor WT1 (refs 2,3). By analogy with other EWS fusion products, the EWS-WT1 chimaera may encode a transcriptional activator whose target genes overlap with those repressed by WT1 (ref. 4). To characterize its functional properties, we generated osteosarcoma cell lines with tightly regulated inducible expression of EWS-WT1. Expression of EWS-WT1 induced the expression of endogenous platelet-derived growth factor-A (PDGFA), a potent secreted mitogen and chemoattractant whose promoter contains the many potential WT1-binding sites. Native PDGFA was not regulated by wild-type WT1, indicating a difference in target gene specificity between this tumour suppressor and its oncogenic derivative. PDGFA was expressed within tumour cells in primary DSRT specimens, but it was absent in Wilms tumours expressing WT1 and Ewing sarcomas with an EWS-Fli translocation. We conclude that the oncogenic fusion of EWS to WT1 in DSRT results in the induction of PDGFA, a potent fibroblast growth factor that contributes to the characteristic reactive fibrosis associated with this unique tumour.
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PMID:The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour. 935 95

We previously demonstrated that after transduction with the v-Ha-ras oncogene and grafting onto nude mouse hosts, primary epidermal keratinocytes with a null mutation in the p53 gene form tumors with increased growth rates and predisposition to malignant conversion relative to p53 wild-type keratinocytes (Weinberg WC, et al., Cancer Res 54:5584-5592, 1994). To further explore the cooperation between p53 loss of function and activation of the ras oncogene, cell lines were established from the normal epidermises of newborn and adult p53-null mice, and parallel subclones were reconstituted with the p53val135 temperature-sensitive mutant. Reconstituted lines C, G, N, and V demonstrated functional p53 transcriptional activator activity at the wild-type-permissive temperature of 32 degrees C, compared with the hygromycin-selected control line X and parental p53-null lines NHK4 and AK1b. Hygromycin-selected subclones, but not the parental lines, made normal skin in vivo; all cell lines made carcinomas after introduction of v-Ha-ras, independent of p53 status. These cell lines were compared in vitro at 32 degrees C to maximize the amount of p53val135 in the wild-type conformation. Expression of v-Ha-ras did not consistently alter p53-mediated transcriptional activity, suggesting tat ras acts downstream or independently of p53. No correlation was observed between p53-mediated transcriptional activity and in vitro growth rates, colony formation after exposure to ultraviolet light, or suppression by normal neighboring keratinocytes. However, keratinocyte cell lines devoid of p53 and expressing v-Ha-ras formed colonies in soft agar; this was blocked at 32 degrees C in all cell lines reconstituted with p53val135. These keratinocyte lines provide a model for exploring the role of p53 and the interaction of p53 and ras in keratinocyte transformation.
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PMID:Cooperation of p53 loss of function and v-Ha-ras in transformation of mouse keratinocyte cell lines. 947 71

Bax and Bcl2 are functionally antagonistic proteins which control apoptosis, whose expression in human tumours could be of prognostic value. We evaluated Bax and Bcl2 expression in 239 breast carcinomas (99 N0, 140 N1/2) with long term follow-up (median 79 months, range 11-140) in relation to clinico-pathologic parameters, clinical outcome, adjuvant therapy and expression of oestrogen receptor protein and p53. The prognostic value of Bax was investigated in the whole series of patients and in subgroups of homogeneously staged and treated patients (i.e., node-negative, N1/2 CMF-treated, N1/2 tamoxifen-treated). Bax immunostaining was cytoplasmic and heterogeneous. Cases were scored as Bax-positive if there were more than 20% reacting cells. High Bax expression was associated with positive nodal status (p = 0.03) and high Bcl2 expression (p = 0.01) and was more frequent in high-grade tumours. In the node-negative subgroup, Bax expression was associated with small tumour size. No association was seen with other parameters or with clinical outcome in any subgroup of patients. Since the apoptotic rate of a tumour is influenced by the ratio Bcl2/Bax, we investigated the combined effects of Bax and Bcl2 expression in relation to clinical outcome. However, no differences in survival were seen in the Bcl2-negative and Bcl2-positive groups when they were subdivided on the basis of the level of Bax expression and vice versa. In experimental systems, p53 is a direct transcriptional activator of the human bax gene. However, we could not observe any relation between Bax and p53 expression. We investigated whether the combined p53/Bax expression could have any prognostic value since it is predicted that tumours with normal p53 expression and concurrent high levels of Bax should be less aggressive and more susceptible to therapy. However, while p53 itself was of prognostic value, Bax expression was not related to prognosis in p53-negative or in p53-positive groups.
Int J Cancer 1998 Feb 20
PMID:Bax immunohistochemical expression in breast carcinoma: a study with long term follow-up. 949 51

The retinoblastoma protein (Rb) acts as a critical cell-cycle regulator and loss of Rb function is associated with a variety of human cancer types. Here we report that Rb binds to members of the AP-1 family of transcription factors, including c-Jun, and stimulates c-Jun transcriptional activity from an AP-1 consensus sequence. The interaction involves the leucine zipper region of c-Jun and the B pocket of Rb as well as a C-terminal domain. We also present evidence that the complexes are found in terminally differentiating keratinocytes and cells entering the G1 phase of the cell cycle after release from serum starvation. The human papillomavirus type 16 E7 protein, which binds to both c-Jun and Rb, inhibits the ability of Rb to activate c-Jun. The results provide evidence of a role for Rb as a transcriptional activator in early G1 and as a potential modulator of c-Jun expression during keratinocyte differentiation.
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PMID:Rb binds c-Jun and activates transcription. 954 46

p53 is a transcriptional activator that plays a key role in the integration of signals inducing cell division arrest and programmed cell death. Moreover, p53 is a tumor suppressor gene, mutations of which are the most commonly detected mutations in diverse malignancies. In order to better understand the significance of p53 mutations to human cancer, we isolated mutant alleles of p53 that had lost transcription factor activity in yeast. These mutant alleles were evaluated for their precise changes, their activity against three different p53 responsive enhancers and their ability to act in a transdominant fashion to the wild type allele. While many of the mutations isolated in yeast resembled those found in human tumors, consistent with the importance of transcription factor activity for p53 in mammalian cells, the mutational spectrum obtained was dependent upon the p53 enhancer employed for the selection. Some mutations specifically inactivated p53 in yeast for a single enhancer element. Virtually all missense mutations tested had a dominant inhibitory effect on wild type p53 in yeast. Since some of these transdominant mutations are virtually unknown in human tumors we conclude that transdominance, per se, fails to predict which mutations occur frequently in cancer.
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PMID:p53 mutations isolated in yeast based on loss of transcription factor activity: similarities and differences from p53 mutations detected in human tumors. 957 92

For cancer gene therapy, it is of primary importance to develop a system to sufficiently and selectively express therapeutic genes in cancer cells. In this study, we showed that an approximately 5.3-kb promoter region of the prostate-specific antigen (PSA) gene can replicate the endogenous expression pattern, although its expression is very weak. We then developed a novel two-step transcriptional activation system in which the PSA promoter drives an artificial transcriptional activator, GAL4-VP16 fusion protein, and it in turn activates transgene expressions under the control of GAL4-responsive elements. By using this system, transgene expressions can be greatly augmented while maintaining prostate-specific expression. Finally, we applied this system to drive an expanded polyglutamine, a potent proapoptotic molecule, to induce apoptosis selectively in PSA-positive prostate cancer cells. This novel system would provide an ideal approach for cancer gene therapy applicable not only to prostate cancer but to other cancers as well.
Cancer Res 1998 Jun 01
PMID:Prostate-specific amplification of expanded polyglutamine expression: a novel approach for cancer gene therapy. 962 59

Loss of heterozygosity (LOH) observed in human tumors strongly suggests the existence of (a) tumor-suppressor gene(s) at the concerned locus. A series of studies has revealed that LOH on the long arm of chromosome 5 (5q) frequently occurs in differentiated gastric adenocarcinomas. Furthermore, it has been shown that the interferon regulatory factor-1 (IRF-1) locus on chromosome 5q31.1 is one of the common minimal regions of LOH in these cancers. IRF-1 is a transcriptional activator that shows tumor-suppressor activity in the mouse. In the present study, we examined the sequence of the IRF-1 gene in 9 cases of histologically differentiated gastric adenocarcinomas, all of which exhibited LOH at the IRF-1 locus. We identified a mis-sense mutation in the residual allele in one case. This mutated form of IRF-1 showed markedly reduced transcriptional activity. In addition, overexpression of wild-type IRF-1 induced cell-cycle arrest, whereas such activity was attenuated in the mutant IRF-1. These results suggest that the loss of functional IRF-1 is critical for the development of human gastric cancers.
Int J Cancer 1998 Aug 12
PMID:Functionally inactivating point mutation in the tumor-suppressor IRF-1 gene identified in human gastric cancer. 967 52

Growth factors of the transforming growth factor-beta (TGF-beta) family inhibit the proliferation of epithelial, endothelial, and hematopoietic cells, and stimulate the synthesis of extracellular matrix components. TGF-beta s are secreted from cells in high-molecular-mass protein complexes that are composed of three proteins, the mature TGF-beta-dimer, the TGF-beta propeptide dimer, or latency-associated protein (LAP), and the latent TGF-beta binding protein (LTBP). Mature TGF-beta is cleaved from its propeptide during secretion, but the proteins remain associated by noncovalent interactions. LTBP is required for efficient secretion and processing of latent TGF-beta and it binds to LAP via disulfide bond(s). LTBP is a component of extracellular matrix microfibrils, and it targets the latent TGF-beta complex to the extracellular matrix. TGF-beta signaling is initiated by proteolytic cleavage of LTBP that results in the release of the latent TGF-beta complex from the extracellular matrix. TGF-beta is activated by dissociation of LAP from the mature TGF-beta. Subsequent signaling involves binding of active TGF-beta to its type II cell surface receptors, which phosphorylate and activate type I TGF-beta receptors. Type I receptors, in turn, phosphorylate cytoplasmic transcriptional activator proteins Smad2 and Smad3, inducing their translocation to the nucleus. Recent evidence suggests that acquisition of resistance to TGF-beta growth inhibition plays a major role in the progression of epithelial and hematopoietic cell malignancies. The role of secretion of TGF-beta in tumorigenesis is more complex. The secretion of TGF-beta s by tumor cells may contribute to autocrine growth inhibition, but on the other hand, it may also promote invasion, metastasis, angiogenesis, and even immunosuppression. Tumor cells may also fail to deposit LTBP:TGF-beta complexes to the extracellular matrix. The elucidation of the mechanisms of the release of TGF-beta from the matrix and its subsequent activation aids the understanding of the pathophysiologic roles of TGF-beta in malignant growth, and allows the development of therapeutic agents that regulate the activity of TGF-beta.
Adv Cancer Res 1998
PMID:Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. 970 8

Ceramide acts as a mediator of programmed cell death in various cell types, but its molecular mechanisms linked to the cell cycle are poorly understood. In this study, we investigated the expression of the p21 gene and its relationship to apoptosis induced by ceramide. In SK-HEP-1 cells, the addition of C6-ceramide resulted in a dose- and time-dependent growth suppression and DNA fragmentation characteristics of apoptosis. p21 protein was induced during that process, while the protein level of p53, known as a transcriptional activator of p21, was not elevated under the same condition. This apoptotic cell death with p21 induction was also observed in the Hep 3B cells lacking functional p53 after exposure to C6-ceramide. These findings suggest that ceramide-induced apoptosis is associated with the upregulation of p21 mRNA and protein in a p53-independent pathway.
Cancer Lett 1998 Jul 17
PMID:Induction of p21 during ceramide-mediated apoptosis in human hepatocarcinoma cells. 971 64


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