Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that human matrix metalloproteinase-1 (MMP1) is a p53 target gene subject to down-regulation (Sun et al. [1999]: J Biol Chem 274:11535-11540]. In the present study, we demonstrate that the down-regulation of the human -83MMP1 promoter fragment by p53 was abolished when the -72AP-1 site was eliminated and that a GAL4-cJun-mediated but not a GAL4-Elk1-mediated induction of pFR-luci was effectively inhibited by p53 suggesting an AP-1 dependent but AP-1 binding independent mechanism. Results from gel mobility shift assays were consistent with an AP-1 binding independent mechanism. We also demonstrate that both p300 and TATA box binding proteins cooperated with the transcription factor AP-1 to induce the promoter of MMP1; however, p53 only inhibited the p300-mediated induction of the MMP1 promoter and the inhibition was -72AP-1 dependent. Furthermore, the down-regulation of the MMP1 promoter and mRNA by p53 could be reversed by p300 and by a p53 binding p300 fragment that had no coactivator activity. Taken together, these results indicate that p53 down-regulates MMP1 mainly by disrupting the communications between the transactivator AP-1 and the basal transcriptional complex, which are partially mediated by p300. Finally, by using p53 truncated mutant constructs, we demonstrate that both the N-terminal activation domain and the C-terminal oligomerization domains of p53 were required for the down-regulation of MMP1 transcription.
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PMID:P53 down-regulates matrix metalloproteinase-1 by targeting the communications between AP-1 and the basal transcription complex. 1510 53

The viral immediate-early transactivator Rta/Orf50 is necessary and sufficient to initiate Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) reactivation from latently infected cells. Since Rta/Orf50 is conserved among all known gamma-2-herpesviruses, we investigated whether the murine gamma-68-herpesvirus (MHV-68) and rhesus monkey rhadinovirus (RRV) homologs can functionally substitute for KSHV Rta/Orf50. (i) Our comparison of 12 KSHV promoters showed that most responded to all three Rta/Orf50proteins, but three promoters (vGPCR, K8, and gB) responded only to the KSHV Rta/Orf50 transactivator. Overall, the activation of KSHV promoters was higher with KSHV Rta than with the RRV and MHV-68 Rta. (ii) Only the primate Rta/Orf50 homologs were able to interfere with human p53-depedent transcriptional activation. (iii) Transcriptional profiling showed that the KSHV Rta/Orf50 was more efficient than it's homologs in inducing KSHV lytic transcription from the latent state. These results suggest that the core functionality of Rta/Orf50 is conserved and independent of its host, but the human protein has evolved additional, human-specific capabilities.
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PMID:Comparison of the Rta/Orf50 transactivator proteins of gamma-2-herpesviruses. 1511 28

The transcriptional co-activator CBP [CREB (cAMP-response-element-binding protein)-binding protein] and its paralogue p300 play a key role in the regulation of both activity and stability of the tumour suppressor p53. Degradation of p53 is mediated by the ubiquitin ligase MDM2 (mouse double minute protein) and is also reported to be regulated by CBP/p300. Direct protein-protein interaction between a central domain of MDM2 and the TAZ1 (transcriptional adaptor zinc-binding domain) [C/H1 (cysteine/histidine-rich region 1)] domain of p300 and subsequent formation of a ternary complex including p53 have been reported previously. We expressed and purified the proposed binding domains of HDM2 (human homologue of MDM2) and CBP, and examined their interactions using CD spectroscopy. The binding studies were extended by using natively purified GST (glutathione S-transferase)-p300 TAZ1 and GST-p53 fusion proteins, together with in vitro translated HDM2 fragments, under similar solution conditions to those in previous studies, but omitting added EDTA, which causes unfolding and aggregation of the zinc-binding TAZ1 domain. Comparing the binding properties of the known TAZ1 interaction partners HIF-1alpha (hypoxia-inducible factor 1), CITED2 (CBP/p300-interacting transactivator with glutamic- and aspartic-rich tail) and STAT2 (signal transducer and activator of transcription 2) with HDM2, our data suggest that TAZ1 in its native state does not serve as a specific recognition domain of HDM2. Rather, unfolded TAZ1 and HDM2 proteins have a high tendency to aggregate, and non-specific protein complexes are formed under certain conditions.
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PMID:The CBP/p300 TAZ1 domain in its native state is not a binding partner of MDM2. 1527 Jul

We previously reported, both in transfected cells and in human T-cell leukemia virus type-2 subtype B infected cells, that the viral transactivator Tax-2B protein could inhibit p53 functions. We have now investigated the mechanism through which Tax-2B represses p53 using GFPTax-2B fusion proteins. We present evidence that Tax-2B inhibition of p53 function is not linked to CREB/ATF activation, but is uniquely correlated with the interaction of CREB binding protein (CBP), but not p300, with the C-terminus of Tax-2B. Wild type, but not a Tax-2B-M47 mutant, inhibits p53 function in adherent cells. We demonstrate that both Tax-2B and Tax-2B-M47 can bind p300, while Tax-2B-M47 is impaired for CBP binding. Importantly, transfection of increasing amounts of CBP but not p300 or p300/CBP-associated factor (P/CAF) could rescue p53 transcriptional activity in the presence of Tax-2B in nonlymphocytic cells. In lymphoid cells, Tax-2B mediated inhibition of p53 is correlated with the NF-kappaB pathway activation and could be prevented by the overexpression of an IkappaBalpha mutant. Given the similarities between the functional domains of CBP and p300, these results are intriguing and suggest that Tax-2B must bind the CR2 domain of CBP, but not that of p300 in order to repress p53.
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PMID:Utilization of the CBP but not the p300 co-activator by human T-lymphotropic virus type-2 Tax for p53 inhibition. 1515 94

The human p63 gene encodes a series of protein isoforms that differ in their N- and/or C-terminal sequences and possess widely varying activities in promoting or repressing p53-related functions and in regulating the proliferation and differentiation of epithelial cells. To gain further information on the role of p63 expression in human tumours, we used quantitative real-time RT-PCR to study individual p63 isoforms in squamous cell carcinomas of the head and neck (SCCHN). In keeping with previous reports, expression of the deltaN- and p63alpha-isoforms predominated and deltaNp63 mRNA was expressed at significantly higher levels in tumours compared to matched normal tissues. Some tumours also expressed the highly efficient transactivator TA- and p63beta-isoforms, and p63beta was significantly increased in tumours compared to matched normal tissue. We could not identify any correlations between different p63-isoform expression patterns and proliferation, p53 status, or telomerase expression. All p63 isoforms could be identified in normal surface epithelium, and micro-dissection showed that the high levels present in basal layers were similar to those seen in tumour tissues. Thus, high-level expression of deltaNp63 in tumour cells may represent maintained expression by the basal cells from which the tumour arose, rather than representing a true over-expression of p63 during tumourigenesis. Tobacco usage, a genotoxic predisposing factor for SCCHN, had no effect on p63 expression in oral epithelium. Taken together, our data indicate that SCCHN maintain expression of high levels of deltaNp63alpha in combination with varying levels of other p63 isoforms, some of which are highly efficient transcriptional activators. The complexity of these p63 expression patterns seen in primary SCCHN indicates that p63 has multifaceted roles in tumour biology.
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PMID:Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck. 1520 86

To identify genes that are stimulated by oncogenic forms of mutant p53, we studied, by microarray analysis and PCR-select subtractive hybridization, gene expression changes in human wild-type (wt) p53-negative immortal 041 fibroblasts infected to stably express p53 mutant 175H. In contrast to the wt p53 transactivator, 175H induced only few and weak, gene expression changes. We report here the stimulation of calmodulin 2 (CaM 2), but not CaM 1 or 3, gene expression specifically in 041 cells. The stimulation of the CaM 2 promoter required the 5' untranslated sequences as well as the integrity of the transactivation domain of 175H. However, direct binding of 175H to the 5'UT in vitro could not be demonstrated.
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PMID:Cell type-specific regulation of calmodulin 2 expression by mutant p53. 1522 11

Serine/threonine protein phosphatase 5 (PP5) appears to play an underappreciated role in the regulation of cellular proliferation. In estrogen-responsive cells, PP5 expression is stimulated by 17 beta-estradiol, and in a variety of p53 wild-type tumor cells the suppression of PP5 expression with ISIS 15534 inhibits growth. To further explore the relationship between PP5 and the development of human cancer, here we tested the effect of elevated PP5 expression on tumor growth using a mouse xenograph model and a stable MCF-7 cell line in which the expression of wild-type PP5 was placed under the control of tetracycline-off regulated transactivator and operator plasmids. In the xenograph model a modest two fold increase in PP5 protein levels significantly enhanced the growth rate of estrogen-dependent tumors, suggesting PP5 plays a positive role in tumor development.
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PMID:Constitutive over expression of serine/threonine protein phosphatase 5 (PP5) augments estrogen-dependent tumor growth in mice. 1537 38

The most often used tetracycline-regulated transgenic mice system requires the generation of two transgenic strains, one carrying an inducible promoter and the other a transactivator. In this study, we report the design of a universal and simplified regulatory gene delivery vector to facilitate the generation of conditional transgenic animals that integrate both the tetracycline regulatory and response elements in a single vector. The newly developed tetracycline reversed transactivator rtTA-M2 was used in all our constructs, based on its highly improved properties with respect to specificity, stability and inducibility. To minimize interference between the different tetracycline-inducible promoters used in this study (tetracycline-responsive element (TRE), TRE-tight, or Tk-tetO) and the rtTA-M2 transactivator, both elements were cloned in opposite directions and separated by a 5 kb human p53 intron. The functionality of this system was confirmed after in vitro transfection in a mammalian cell line. Overall induction by the tetracycline-responsive element promoter was significantly higher than that induced by the newly developed TRE-tight promoter. However, the TRE-tight promoter showed a significantly tighter expression with minimal background, and still maintained high induction levels. The minimal Tk-tetO promoter showed a very weak induction capacity. Our study demonstrates that this combination of elements, placed in a single vector is sufficient for delivering a functional tetracycline-inducible system to a mammalian cell line. Moreover, additional modifications to this regulatory gene delivery system, such as the introduction of specific cloning sites and selection markers, have been designed with the idea of creating a simplified and universal inducible system to facilitate the generation of conditional transgenic, knock-out, and knock-in animals.
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PMID:Tetracycline-inducible expression systems for the generation of transgenic animals: a comparison of various inducible systems carried in a single vector. 1548 39

Splenic marginal zone lymphoma (SMZL) is a lymphoma type of putative marginal zone B-cell origin. No specific genetic alterations have yet been demonstrated in SMZL. Clinically, SMZL is a low-grade B-cell non-Hodgkin lymphoma. However, the presence of p53 mutation, 7q22-7q32 deletion or the absence of somatic hypermutations of immunoglobulin genes has been correlated with a worse prognosis. In this study, we analyzed genome-wide gene expression of 24 cases of SMZL using the microarray technique. The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated. These data were confirmed by real-time PCR and immunohistochemical staining of tissue sections. The absence of concordant high expression of the MAP kinases, the signaling cascade leading to AP-1 up-regulation, suggests autoregulation of the AP-1 transcription factors and an important role in SMZL oncogenesis. High expression of Notch2, a transcription factor that induces marginal zone B-cell differentiation, is highly suggestive for a marginal zone B-cell origin of SMZL. In addition, SMZL with the 7q deletion showed high expression of TGF-beta1 and low expression of the DNA helicase XPB, a crucial part of the nucleotide excision repair complex, possibly explaining the more aggressive clinical course of those cases.
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PMID:Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma. 1550 68

A molecular mechanism to explain reduced KAI1 expression in invasive and metastatic tumour cells remains elusive. In this report, we extend an earlier study in bladder cells to confirm that a 76 bp region of the KAI1 promoter (residues -922 to -847), with binding motifs for p53, AP1 and AP2, is required for high level activity of a KAI1 reporter in prostate cancer cell lines. Gel shift and supershift experiments supported binding of p53, junB and heterodimers of AP2alpha/AP2gamma or AP2beta/AP2gamma to this sequence. Introduction of mutations into specific motifs demonstrated an essential requirement for p53 and junB to reporter activity, and that functional synergy between these two factors enhanced activity. A further elevation of reporter activity required AP2. Roles of individual p53, junB and AP2 proteins, as well as functional synergy between p53 and junB, were confirmed in transfection experiments. Western blotting analysis showed that an absence of wild-type p53, and/or a loss of junB and AP2 protein expression, correlated with downregulation of KAI1 mRNA levels in a series of prostate cancer cell lines. A loss of p53 function and/or expression of junB, combined with reduced expression of specific AP2 proteins may underly downregulated KAI1 expression in tumour cells.
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PMID:KAI1 promoter activity is dependent on p53, junB and AP2: evidence for a possible mechanism underlying loss of KAI1 expression in cancer cells. 1558 Feb 98


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