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)

Small interfering RNA (siRNA) is widely recognized as a powerful tool for targeted gene silencing. However, siRNA gene silencing occurs during transfection, limiting its use is in kinetic studies, deciphering toxic and off-target effects and phenotypic assays requiring temporal, and/or spatial regulation. We developed a novel controllable siRNA (csiRNA) that is activated by light. A single photo removable group is coupled during oligonucleotide synthesis to the 5' end of the antisense strand of the siRNA, which blocks the siRNA's activity. A low dose of light activates the siRNA, independent of transfection resulting in knock down of specific target mRNAs and proteins (GAPDH, p53, survivin, hNuf2) without stimulating non-specific effects such as regulated protein kinase PKR and induction of the interferon response. We demonstrate survivin and hNuf2 csiRNAs temporally knockdown their mRNAs causing multinucleation and cell death by mitotic arrest, respectively. Furthermore, we demonstrate a dose-dependent light regulation of hNuf2 csiRNA activity and resulting phenotype. The light controllable siRNAs are introduced into cells using commercially available reagents including the MPG peptide based delivery system. The csiRNAs are comparable to standard siRNAs in their transfection efficiency and potency of gene silencing. This technology should be of interest for phenotypic assays such as cell survival, cell cycle regulation, and cell development.
 ...
PMID:Light controllable siRNAs regulate gene suppression and phenotypes in cells. 1649 69

The incidence of hepatocellular carcinoma (HCC) varies widely worldwide. Chronic infection with hepatitis B virus (HBV) and exposure to aflatoxins in foodstuffs are the main risk factors. AAG to AGT transversion at codon 249 of the P53 gene arg-ser (249ser) has been identified as a hotspot, reflecting DNA damage caused by aflatoxin B1 metabolites in HCC. Because HBV infection is often endemic in high aflatoxin exposure areas, it is still not clear whether HBV acts as a con-founder or as a synergistic partner in the development of the 249ser P53 mutation. Serum levels of soluble interleukin 2 receptor (sIL-2R) correlated with the progression of liver cirrhosis independently of its etiology. This fact may reflect the stimulation of T-lymphocytes, monocytes and macrophages in liver cirrhosis. The inter-relationship among aflatoxin exposure, HBV & HCV infections, P53 & sIL-2R in patients with liver cirrhosis and hepatocellular carcinoma was studied. The results revealed significant increase in serum levels of mutant P53, sIL-2R and aflatoxin B1 in patients with cirrhosis and those with HCC compared to the controls. HCC patients showed levels of all the three parameters significantly higher than both cirrhotics and controls (P<0.001). Correlations were found between serum aflatoxin B1, mutant P53 and sIL-2R in HCC group. The results were discussed.
 ...
PMID:Clinical significance of aflatoxin, mutant P53 gene and sIL-2 receptor in liver cirrhosis and hepatocellular carcinoma. 1660 12

Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include telomerase, mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), mutated B-Raf, mutated EGF receptor, and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause inactivation, destabilization and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in various preclinical tumor models. One Hsp90 inhibitor, 17-AAG, is currently in Phase II clinical trial and other inhibitors will shortly be entering the clinic. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Identification of benzoquinone ansamycins as the first Hsp90 inhibitors allowed investigators to determine the biologic effects, at first in vitro and then in vivo, of pharmacologic inhibition of Hsp90. These studies rapidly enhanced our understanding of Hsp90 function and led to the identification of radicicol as a structurally distinct Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.
 ...
PMID:Using natural product inhibitors to validate Hsp90 as a molecular target in cancer. 1684 53

Development of new molecular target therapeutic agents is expected to improve clinical outcome, ideally with efficacy in both single and combined treatment modalities. Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp90) may provide a strategy for enhancing tumor cell radiation sensitivity. Therefore, we have investigated the effects of Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on radiation sensitivity of human tumor cells in vitro. We evaluated the effects of 17-AAG using oral squamous cell carcinoma (OSCC) cell lines (HSC2, HSC3 and HSC4), including two types of SAS cells with a wild-type (SAS/neo), or a mutated p53 status (SAS/Trp248). Apoptosis and clonogenic survival were examined after exposure of the cells to radiation. For mechanistic insight, we analyzed cell cycle, several signaling factors and molecular markers including Akt, Raf-1, p38 MAPK, Cdc25B, Cdc25C, Cdk2 and p21. Treatment of OSCC cell lines with 17-AAG resulted in cytotoxicity and, when combined with radiation, enhanced the radiation response. However, the responses depended on p53 status. 17-AAG enhanced the radiation sensitivity significantly and induced apoptosis in the SAS/neo cell which has a wild-type p53. But the radiation sensitizing effect of 17-AAG was limited in the SAS/Trp248 cell which has a mutated p53. We also measured the total levels of several prosurvival and cell cycle signaling proteins. Akt, Raf-1 and Cdc25C expression were down-regulated in 17-AAG-treated cells. These data indicate that 17-AAG inhibits the proliferation and enhances the radiation sensitivity of human OSCC cells in various levels. However, enhancement of radiation sensitivity by the Hsp90 inhibitor depended on p53 status. Therefore, Hsp90 therapy combined with radiation might synergize with conventional therapies in patients with wild-type p53.
 ...
PMID:P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines. 1701 41

In a series of colorectal cancer cell lines, both necrosis and apoptosis were induced upon exposure to oxaliplatin, and enhanced by co-administration of the Hsp90 inhibitor 17-AAG. We analyzed the effects of these interventions on the cell cycle, and found that oxaliplatin treatment caused G1 and G2 arrest in HCT116 cells, and S-phase accumulation in two p53-deficient cell lines (HT29 and DLD1). Addition of 17-AAG enhanced cell cycle effects of oxaliplatin in HCT116, and induced G1 arrest and decrease in S-phase population in the other cell lines. Analysis of cell cycle proteins revealed that the major difference between the cell lines was that in HCT116, 17-AAG resulted in profound inhibition of expression and phosphorylation of late G1 proteins cyclin E and cdk2, with no effect on p21/WAF1 induction. Consistent with these, an HCT116 p53(-/-) line, lacking p21, showed resistance to oxaliplatin, failure to enter apoptosis, and an accumulation of cells in S-phase. Introduction of p21 in these cells caused reversal of that phenotype, including restoration of the G1 block and re-sensitization to oxaliplatin. Inhibition of G1/S progression using cdk2 inhibitor also enhanced oxaliplatin cytotoxicity. We conclude that in colon cancer cells with impaired p53 function, interventions directed to cycle arrest in G1 may potentiate oxaliplatin activity.
 ...
PMID:Inhibition of G1/S transition potentiates oxaliplatin-induced cell death in colon cancer cell lines. 1734 30

The spindle checkpoint that monitors kinetochore-microtubule attachment has been implicated in tumorigenesis; however, the relation between the spindle checkpoint and cell death remains obscure. In BUB1-deficient (but not MAD2-deficient) cells, conditions that activate the spindle checkpoint (i.e., cold shock or treatment with nocodazole, paclitaxel, or 17-AAG) induced DNA fragmentation during early mitosis. This mitotic cell death was independent of caspase activation; therefore, we named it caspase-independent mitotic death (CIMD). CIMD depends on p73, a homologue of p53, but not on p53. CIMD also depends on apoptosis-inducing factor and endonuclease G, which are effectors of caspase-independent cell death. Treatment with nocodazole, paclitaxel, or 17-AAG induced CIMD in cell lines derived from colon tumors with chromosome instability, but not in cells from colon tumors with microsatellite instability. This result was due to low BUB1 expression in the former cell lines. When BUB1 is completely depleted, aneuploidy rather than CIMD occurs. These results suggest that cells prone to substantial chromosome missegregation might be eliminated via CIMD.
 ...
PMID:BUB1 mediation of caspase-independent mitotic death determines cell fate. 1762 Apr 10

Hsp90 is an evolutionarily conserved and ubiquitously expressed molecular chaperone that mainly modulates, along with a group of co-chaperones, the general platform of protein folding and prevents the nonspecific aggregation of misfolded or unfolded proteins. In the voluminous Hsp90 clientele, a large variety of important regulatory proteins can be identified, including many whose deregulation may lead to cancer initiation and progression, such as the oncogenic clients pp60(v-src), Bcr-Abl, mutated p53, ErbB2 (Her-2), Akt, Flt3, HIF-1alpha and B-Raf. Therefore, inhibition of Hsp90 function offers the prospect of simultaneously disrupting multiple signaling pathways directly implicated in the development of malignant phenotypes. During the last few years, there has been a major focus on the development of Hsp90 specific inhibitors. This started with the discovery that certain natural products could specifically disrupt Hsp90 chaperone activities. The benzoquinone ansamycin antibiotic geldanamycin and its less toxic derivative 17-AAG have been shown to possess strong anti-proliferative and apoptotic activity in cancer cells, whereas 17-AAG has demonstrated potent anti-tumor activity in several human xenograft models, including breast, prostate and colon cancer. In an effort to overcome difficulties with drug toxicity and solubility, a number of novel bioengineered 17-AAG analogues, such as 17-DMAG and IPI-504, and small-molecule inhibitors, including purine and pyrazole derivatives, have emerged from rational drug design followed by high-throughput screening approaches. 17-AAG was the leader inhibitor to enter and successfully complete phase I clinical trials, thus demonstrating that Hsp90 constitutes a valid drug target for cancer therapy. This review includes information on the current model of ternary interactions between Hsp90, client proteins and a vast array of co-chaperones followed by a list of characteristic inhibitors and ongoing clinical trials reported thus far.
 ...
PMID:Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. 1822 Jul 46

The spindle checkpoint, which monitors kinetochore-microtubule attachment, is required for high fidelity of chromosome transmission. A failure in this mechanism causes aneuploidy, thereby promoting progression to tumorigenesis. However, the cell death mechanism that prevents the aneuploidy caused by failure of the spindle checkpoint is yet unknown. We have recently identified a novel type of mitotic cell death, which we term caspase-independent mitotic death (CIMD). In BUB1-deficient (but not MAD2-deficient) cells, CIMD is induced by conditions that activate the spindle checkpoint (i.e., cold shock or treatment with nocodazole, paclitaxel or 17-AAG [17-allylaminogeldanamycin]). CIMD depends on p73, a homolog of p53, but not on p53. It also depends on the apoptosis-inducing factor (AIF) and endonuclease G (Endo G), which are effectors of caspase-independent cell death. When BUB1 is completely depleted, aneuploidy occurs instead of CIMD. We propose that CIMD can be the cell death mechanism that protects cells from aneuploidy by inducing the death of cells prone to substantial chromosome missegregation. Our study also shows that previous evaluations of the spindle checkpoint activity in mutant or cancer cells by monitoring mitotic index could be misleading.
 ...
PMID:Caspase-independent mitotic death (CIMD). 1841 23

The p53 mutation in salamanders can be used as an indicator of arsenic contamination. The influence of arsenic exposure was studied on mutation of tumor suppressor gene in salamanders collected from several As-contaminated mine areas in Korea. Salamander eggs and larvae were exposed to arsenic in a toxicity test, and teratogenic salamanders found in heavy metal- and As-contaminated water from As-Bi mines were evaluated using PCR-SSCP to determine if they would be useful as an ecological indicator species. Changes in amino acids were shown to have occurred as a result of an arsenic-accumulating event that occurred after the DNA damage. In addition, both of the Hynobius leechii exposed groups were primarily affected by forms of skin damage, changes in the lateral tail/dorsal flexure and/or abnormality teratogenesis. Single-base sense mutation in codons 346 (AAG: Lys to ATG: Met), 224 (TTT: Phe to TTA: Leu), 211 (ATG: Met to AAG: Lys), 244 (TTT: Phe to TTTG: insertion), 245 (Glu GAG to Gln CAG) and 249 (TGT Cys to TGA stop) of the p53 gene were simultaneously found in mutated salamanders. Based on the results of our data illustrating the effect of arsenic exposure on the p53 mutation of salamanders in arsenic-contaminated mine areas, these mutated salamanders can be used as potential ecological indicators in the arsenic-contaminated ecosystems.
 ...
PMID:Effect of arsenic on p53 mutation and occurrence of teratogenic salamanders: their potential as ecological indicators for arsenic contamination. 1920 79

Disruption or loss of tumor suppressor gene TP53 is implicated in the development or progression of almost all different types of human malignancies. Other members of the p53 family have been identified. One member, p73, not only shares a high degree of similarity with p53 in its primary sequence, but also has similar functions. Like p53, p73 can bind to DNA and activate transcription. Using PCR-SSCP and gene sequencing, we analyzed the TP53 and TP73 genes in a case of a grade III anaplastic astrocytoma that progressed to glioblastoma. We found a deletion of AAG at position 595-597 of TP53 (exon 6), resulting in the deletion of Glu 199 in the protein and a genomic polymorphism of TP73, identified as an A-to-G change, at position E8/+15 at intron 8 (IVS8-15A>G). The mutation found at exon 6 of the gene TP53 could be associated with the rapid tumoral progression found in this case, since the mutated p53 may inactivate the wild-type p53 and the p73alpha protein, which was conserved here, leading to an increase in cellular instability.
 ...
PMID:Concurrent sequence variation of TP53 and TP73 genes in anaplastic astrocytoma. 1987 67


<< Previous 1 2 3 4 5 6 Next >>