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 tested the ability of synthetic peptides derived from p21(WAF1), fused to the internalization peptide sequence derived from Antennapedia, to inhibit the growth of cancer cells in two human ovarian cancer cell lines expressing wild-type p53 or not. Two fused peptides corresponding to p21(WAF1) regions 17-33 and 63-77 inhibited cell growth in both cell lines while the same peptides without the internalization sequence were inactive. The fused peptides prevented growth at concentrations which inhibited cyclin-dependent kinase 2 and cdc2 activity, thus demonstrating that the peptides act by mimicking the action of p21(WAF1) on kinases. This study illustrates the potential pharmacological use of small peptides fused with the Antennapedia internalization sequence in proliferative disorders. The approach may be extended to other diseases in which cell penetration of a peptide may be of therapeutic benefit. More stable drug-like molecules with better pharmacological properties could be designed based on the results obtained with peptides.
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PMID:p21WAF1-derived peptides linked to an internalization peptide inhibit human cancer cell growth. 910 43

The p53 tumor suppressor protein is a sequence-specific transcriptional activator of target genes. Exposure of cells to DNA damage results in accumulation of biochemically active p53, with consequent activation of p53-responsive promoters. In order to study how the transcriptional activity of the p53 protein is regulated in vivo, a transgenic mouse strain was generated. These mice harbor the p53-dependent promoter of the mdm2 gene, fused to a lacZ reporter gene. Induction of lacZ activity by DNA damage (ionizing radiation) was monitored in embryos of different p53 genotypes. The transgenic promoter was substantially activated in vivo following irradiation; activation required functional p53. The activation pattern became more restricted with increasing embryo age, as well as with the state of differentiation of a given tissue. Generally, maximal p53 activation occurred in rapidly proliferating, relatively less differentiated cells. A striking extent of haploinsufficiency was revealed-induction of promoter activity was far less efficient in mice carrying only one wild-type p53 allele. This suggests that normal levels of cellular p53 are limiting, and any further reduction already compromises the p53 response significantly. Thus, the activation potential of p53 is tightly controlled in vivo, both spatially and temporally, and an important element in this control is the presence of limiting basal levels of activatable p53.
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PMID:Transgenic mouse model for studying the transcriptional activity of the p53 protein: age- and tissue-dependent changes in radiation-induced activation during embryogenesis. 913 53

The general transcription initiation factor TFIID contains the TATA-binding protein (TBP) and TBP-associated factors (TAFs) implicated in the function of gene-specific activators. Previous studies have indicated that a hamster cell line (ts13) with a point mutation in the TAF(II)250/CCG1 (TAF(II)250) gene shows temperature-sensitive expression of a subset of genes and arrests in late G1 at 39.5 degrees C. Here, we report the identification of cell cycle-specific (G1-specific) genes that appear to be regulated directly through TAF(II)250 both in vivo and in vitro. Transcription rates of several cell cycle-regulatory genes were determined by run-on assays in nuclei from ts13 cells grown at permissive (33 degrees C) and nonpermissive (39.5 degrees C) temperatures. Temperature-dependent differences in transcription rates were observed for cyclin A, D1, and D3 genes. In transient-transfection assays, the human cyclin D1 promoter fused to a luciferase reporter showed a temperature-dependent reduction in activity in ts13 cells but not in parental BHK cells. In in vitro assays, upstream sequence-dependent transcription from the human cyclin D1 promoter was significantly reduced in ts13 nuclear extracts preincubated at 30 degrees C but not in similarly treated BHK nuclear extracts, and transcription in the ts13 extract was restored by addition of an affinity-purified human TFIID. Preincubation of the ts13 nuclear extracts did not affect the function of several GAL4-activation domain fusion proteins (GAL4-VP16, GAL4-p65, and GAL4-p53) on either the adenovirus major late or cyclin D1 core promoter bearing GAL4 sites, further indicating that the effect of the TAF(II)250 mutation is both core promoter and activator specific.
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PMID:The ts13 mutation in the TAF(II)250 subunit (CCG1) of TFIID directly affects transcription of D-type cyclin genes in cells arrested in G1 at the nonpermissive temperature. 915 27

In a previous study, we explored the mechanisms of SNR6 gene activation by grafting a heterologous DNA-binding domain, GAL4-(1-147), to various components of the yeast RNA polymerase III transcription system. Here, we demonstrate that a modified SNR6 gene harboring GAL4-binding sites (UAS(G)-SNR6) can be efficiently activated via an intervening, unrelated protein-protein interaction, thus laying the foundations of a RNA polymerase III-based two-hybrid system. In a model system, the interacting proteins recruiting TFIIIC to DNA were PRP21 and PRP9 or PRP21 and PRP11. Mutations affecting the interaction between PRP21 and PRP9, or PRP21 and PRP11 decreased UAS(G)-SNR6 activation level proportionally. RNA polymerase II transcriptional activators, like GAL4, VP16 or p53, fused to GAL4 DNA-binding domain, did not activate the UAS(G)-SNR6 gene. However, GAL4 strongly activated UAS(G)-SNR6 when GAL80, an interacting protein, was fused to TFIIIC. This result indicates that this two-hybrid system can be used to assess the interactions between RNA polymerase II regulatory proteins and their partners.
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PMID:A RNA polymerase III-based two-hybrid system to study RNA polymerase II transcriptional regulators. 915 67

The etiopathogenesis of neoplastic diseases is characterized by its multiple nature. Multiple biological and physical agents have been identified as initiating or promoting neoplastic mechanisms. However, they all appear to have common molecular basis, granting genetic instability and causing somatic derangements to preneoplastic and tumor cells. Target genes implicated in cellular transformation and tumor progression have been divided into two categories: proto-oncogenes (that when activated become dominant events characterized by gain of function) and tumor suppressor genes (recessive events characterized by the loss of function). Alteration in proto-oncogenes and tumor suppressor genes seem equally prevalent among human cancers. Multiple mutations appear to be required to conform the malignant phenotype. It is, therefore, conceivable to view cancer as fundamentally a genetic disease entailing inherited (also called "germline") or acquired (also termed "somatic") mutations of genes in these two categories. The concept of tumor suppressor genes was established in studies with somatic cell hybrids, revealing that when malignant cells were fused with normal cells some of the hybrids were nontumorigenic. Clinically, the existence and relevance of this category of genes was based on epidemiological studies of the intraocular childhood tumor retinoblastoma, and it was postulated that two independent events were needed to inactivate a given gene. It was further shown that, in general, that was achieved by an allelic loss followed by a point mutation of the remaining allele. A family of genes has been characterized that follows this "two-hit" model including the two prototype suppressors genes: the retinoblastoma (RB) and the TP53 (also known as p53) genes. These genes encode a variety of molecules with distinct biological properties, including cell cycle regulation and cellular differentiation. Germline and somatic mutations of these genes appear to be the most common abnormalities found in human cancer including bladder neoplasms. More recent studies have shown that inactivation of some of these genes (i.e., TP53) occurs in bladder tumors that have a more aggressive clinical outcome and poor prognosis. In the following subheadings, the authors have reviewed the molecular abnormalities associated with these recessive genes in bladder tumors and discuss the potential clinical use of their detection. The implementation of objective predictive assays to identify these alterations in clinical material will enhance the ability to assess tumor biological activities and to design effective treatment regimens. The need now is to translate this newly developed scientific knowledge into diagnostic and therapeutic strategies, which, in turn, will enhance quality of life and prolong patient survival.
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PMID:Alterations of tumor suppressor genes in bladder cancer. 917 73

Transcriptional activation of the human c-myc gene by SV40 large T antigen was examined using HepG2 cells by co-transfecting a T antigen expression plasmid with a myc-CAT construct containing the 2.3-kb upstream region from the P1 promoter and the P2 promoter region fused to the CAT gene. T antigen increased the basal activity of the P2 promoter region containing the E2F binding site, but both the P2 promoter region and the upstream region from the P1 promoter were important for overall activation by T antigen. CAT assay using mutated T antigen lacking p53 or the RB binding site indicated that p53 or RB was not mainly involved in transcriptional activation of the c-myc gene. It appears that activation of the c-myc gene by T antigen is probably dependent upon E2F and a cellular factor through a mechanism which is independent of binding of T antigen to p53 and RB.
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PMID:Transcriptional activation of the human c-myc gene by simian virus 40 large T antigen without binding to p53 and RB proteins in the transient expression system. 919 53

Out of a total of 21 exencephalic p53-deficient embryonic and newborn mice, 6 (28.6%) possessed fused maxillary incisor teeth. On histological analysis of the 5 examples seen on day 19.5 of gestation and newborn mice, 3 varieties were observed: an example of 'simple' fusion, 3 examples of simple fusion each of which contained a 'dens in dente' ('tooth within a tooth'), and a single example in which the fused teeth were associated with a median supernumerary incisor tooth which, while deeply indenting the labial surface of the fused teeth, was in all locations a completely separate unit. 3-D reconstructions of the fused teeth demonstrated that they were all of the fusio subtotalis variety. No gross abnormalities were observed in the other dentition in these mice. It is noted that in mice fused maxillary incisor teeth are relatively commonly associated with both hypervitaminosis A-induced and trypan blue-induced exencephaly. It is believed that the presence of dens in dente within fused maxillary incisor teeth has only once been reported in mice, and the association between fused maxillary incisor teeth and a median supernumerary incisor tooth has not previously been reported in this species.
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PMID:Analysis of fused maxillary incisor dentition in p53-deficient exencephalic mice. 927 59

The hdm2 gene is overexpressed in a variety of human tumors. Its gene product localizes predominantly to the nucleus, where it acts as an inhibitor of the p53 tumor suppressor gene product. It is shown here that the hdm2 oncoprotein constantly shuttles between the nucleus and the cytoplasm. Shuttling of hdm2 does not depend on its interaction with p53. Nuclear export of hdm2 is mediated by a signal sequence similar to the nuclear export signal of the rev protein from human immunodeficiency virus and other lentiviruses. Mutation of this signal sequence abolishes detectable nucleo-cytoplasmic shuttling. When fused to a carrier protein, the hdm2 signal sequence can mediate nuclear export after intranuclear microinjection into HeLa cells. The export of hdm2 can be blocked by a competitive inhibitor of rev export, arguing that the export pathways for hdm2 and rev are either overlapping or identical. Inhibition of its export modifies the ability of hdm2 to block p53-mediated transcriptional activation, and hdm2's export function is required to accelerate the degradation of p53. Thus the rev nuclear export pathway may be used to regulate an oncogene product's activity and modulate cellular growth.
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PMID:Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein. 943 Jun 46

We have generated a transgenic mouse model in which female mice develop ductal mammary adenocarcinomas and male mice develop prostatic adenocarcinomas by using a transgene containing the hormone-responsive rat prostatic steroid binding protein 5' flanking region C3(1) fused to the simian virus 40 (SV40) large T antigen. We have identified some genetic alterations during mammary and prostate tumor progression: (i) p53 is functionally inactivated during mammary cancer development without p53 mutations; (ii) Alterations in apoptosis during mammary tumor progression are p53 and bcl-2 independent; (iii) Ha-ras mutations occur early in the development of prostate cancer. This unique animal model offers the opportunity to study multistep tumorigenesis in these organs.
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PMID:Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model. 945 74

Activation of the transcription factor NF-kappaB in response to a variety of stimuli is governed by the signal-induced proteolytic degradation of NF-kappaB inhibitor proteins, the IkappaBs. We have investigated the sequence requirements for signal-induced IkappaBalpha phosphorylation and proteolysis by generating chimeric proteins containing discrete sub-regions of IkappaBalpha fused to the IkappaBalpha homologue Bcl-3, the transcription factor NF-kappaB1/p50 and the tumour suppressor protein p53. Using this approach we show that the N-terminal signal response domain (SRD) of IkappaBalpha directs their signal-dependent phosphorylation and degradation when transferred to heterologous proteins. The C-terminal PEST sequence from IkappaBalpha was not essential for induced proteolysis of the chimeric proteins. A deletion analysis conducted on the SRD identified a 25 amino acid sub-domain of IkappaBalpha that is necessary and sufficient for the degradative response in vivo and for recognition by TNFalpha-dependent IkappaBalpha kinase in vitro . The results obtained should prove instrumental in the further characterization of IkappaB-specific kinases, as well as the E2 and E3 enzymes responsible for IkappaBalpha ubiquitination. Furthermore, they suggest a novel strategy for generating conditional mutants, by targetting heterologous proteins for transient elimination by the IkappaBalpha pathway.
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PMID:Signal-dependent degradation of IkappaBalpha is mediated by an inducible destruction box that can be transferred to NF-kappaB, bcl-3 or p53. 951 45


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