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

Apoptosis, known as programmed cell death, is defined as a cell's preferred form of death under hectic conditions through genetically conserved and complex pathways. There is a decisive balance between stimulatory and inhibitory signaling pathways to maintain homeostasis in cells. In order to shift the balance towards apoptosis, the modulation of both apoptotic and anti-apoptotic pathways represents an attractive target for cancer therapeutics. Currently, chemotherapy and radiotherapy are among the most commonly used treatment modalities against lung cancer. Tumor suppressor gene, p53, is required in order for both of these treatment methods to work as anti-tumor agents. As a result, tumors lacking p53 display resistance to both chemotherapy and radiotherapy. However, death ligands induce apoptosis regardless of p53 status of cells. Thus, these methods constitute a complementary therapeutic approach to currently employed conventional treatment modalities. At present, death ligands are being evaluated as potential cancer therapeutic agents. Since resistance to tumor necrosis factor (TNF)-alpha-mediated apoptosis represented an obstacle for the treatment of patients with lung carcinoma in the earlier attempts, an extensive research was recently initiated to understand molecular mechanism of TNF-alpha signaling. NF-kappaB transcription factors have been demonstrated to modulate the apoptotic program, mostly as blockers of apoptosis in different cell types. In this review, we concentrate on the current progress in the understanding of TNF-alpha-mediated apoptosis for lung carcinoma. Representative models of NF-kappaB-inhibiting gene therapy strategies from various labs including ours are also provided as examples of up-to-date approaches to defeat TNF resistance. In order to give the reader better understanding and appreciation of such approaches, previously unpublished in vivo assays are also incorporated into this review. Current progress in clinical trials using adenovirus-mediated delivery of TNF-alpha is also discussed.
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PMID:Fundamental principals of tumor necrosis factor-alpha gene therapy approach and implications for patients with lung carcinoma. 1508 85

The response of cancer to ionizing radiation treatment varies in a manner not fully explained by standard clinical, demographic, or histologic factors. Response may be related to intrinsic biologic capability of the tumor cells and/or the host immune or stromal support tissues. The availability of molecular biological methods to detect specific tumor-related genetic alterations and altered protein expression has prompted a search for molecular markers that accurately predict tumor response to therapy. Tumor suppressor genes and oncogenes such as p53 and Cyclin D1, key components of pathways that control tumor behavior, such as epidermal growth factor receptor and apoptotic factors including bcl-2, markers of proliferation (Ki-67), and markers of angiogenesis such as vascular endothelial growth factor have been examined. To date, results for each of these are mixed. This is not surprising given the complexity of the biologic system of tumor response to damage and the multitude of factors that contribute to the diversity of clinical presentation of disease. This manuscript reviews the literature to date in an effort to summarize results and suggest the direction for further study.
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PMID:Molecular markers of radiation effectiveness in head and neck squamous cell carcinoma. 1509 59

Tumor suppressor gene p53 is one of the most specific genetic alterations occurring in osteosarcoma pathogenesis. It is thought to be an early and key step in the tumorigenesis of osteosarcoma. However, whether the p53 status is a marker predictive of response to therapy and a marker of prognostic value remains controversial. The choice of p53 status detection method certainly account for discrepancies. The authors used a simple functional assay (functional analysis of separated alleles in yeast) on the tumor sample of an 8-year-old girl presenting with an osteosarcoma of the tibia. While making it possible to exclude the presence of a germline mutation, FASAY indicated the presence of a somatic p53 mutation lacking transcriptional activity on p21 and bax target genes. FASAY also strongly suggested a loss of heterozygosity p53, which was confirmed by cytogenetic analysis. Sequencing of cDNA extracted from yeast colonies containing mutated p53 identified a 213 stop mutation in exon 6. Despite these p53 alterations, the child is still in complete remission after a follow-up of 48 months.
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PMID:Identification of a transcriptionally inactive p53 mutant by functional analysis of separated alleles in yeasts (FASAY) in a child osteosarcoma tumor: a case report. 1520 94

Tumor suppressor genes can promote p53-mediated apoptosis. Apoptosis is an important protective mechanism for normal cell growth. Aberrant regulation of p53 expression is linked to cancer development. The loss of function of p53 often results in tumorigenicity. It is reported that the high incidence of tumors in p53-deficient animals is highly attributed to p53-induced apoptosis. Malignancies that retain the wild-type p53 gene are associated with the biologic activity of p53 function. Most cancer cells show defects in p53 or inhibition in the associated pathways. A lot of effort has been focused on reactivating mutant p53, or recombinant technique to incorporate p53 in cells. Regulation of p53 has been described at both transcription and translation level. Activation of the p53 pathway appears to be an effective approach in inhibiting tumor development. In the present study, we have reviewed the recent developments of specific compounds that can regulate p53 expression and its function in cell growth and development. Integral to this is the function of other proteins that affect p53 activity.
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PMID:Activation of p53 by specific agents in potential cancer therapy. 1577 20

Vasostatin, a fragment of calreticulin, was transfected in the BON cell line to evaluate the feasibility of using it for gene therapy in neuroendocrine tumors. Vasostatin transfected cells were subcutaneously inoculated in nude mice. Burkitt lymphoma cell line, CA46, colorectal adenocarcinoma cell line, SW480, as well as endothelial cells PAE and SVEC4 were used for evaluating the function of vasostatin. The results demonstrated that vasostatin transfer caused enhanced malignant behavior of neuroendocrine tumor cell line, BON. Cell adhesion, spreading and cellular invasion were also enhanced in vasostatin-expressing BON cells. Tumor suppressor genes including p53, nm23, Rb and vinculin were down-regulated. Moreover, cell cycle regulatory protein, p27kip1, and cell differentiation-related protein kinase, PKR, were also significantly down-regulated. Furthermore, expression of NKG2D ligands, MICA and MICB, were down-regulated. Mice implanted with vasostatin-expressing BON cells showed an earlier and faster tumor growth compared to wild type. Anti-proliferative effects of vasostatin could not be proven in other cells except in PAE. These results indicated that vasostatin does probably not have a tumor growth inhibitory effect by itself, but rather modulates processes which are necessary for tumor growth. Therefore, one should be very careful when using vasostatin as an anti-tumoral agent in clinical trials, at least for neuroendocrine tumors.
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PMID:Gene transfer of vasostatin, a calreticulin fragment, into neuroendocrine tumor cells results in enhanced malignant behavior. 1629 70

Tumor suppressor genes play a prominent role in the modification and progression of urinary bladder carcinogenesis as a result of classic genetic alterations. Little is known about the potential significance of epigenetic events, mediated by DNA hypermethylation. This prompted our investigation to explore the global Alu methylation and the promoter methylation of the novel putative tumor suppressor genes caveolin-1 and hDAB2IP, and of p53 in transitional cell carcinomas (TCC), squamous cell carcinomas and undifferentiated small cell carcinomas of the urinary bladder. Quantitative GeneScan analysis revealed that the various histopathological tumor entities showed considerable interindividual variations in the global methylation, but the overall rate did not significantly differ between the various cancer subtypes. With methylation-specific PCR, a high frequency of methylation of the promoter region of the caveolin-1 gene was detected in undifferentiated small cell carcinomas (50%) and in squamous cell carcinomas (25.9%), while TCC were found not to be methylated. By immunohistochemistry, all squamous cell carcinomas showed a strong diffuse overexpression of caveolin-1, whereas undifferentiated small cell cancers lacked any expression. High-grade, high-stage TCC disclosed a higher incidence (60%) and a substantially stronger expression than low-grade, low-stage TCC (42.9%). Our findings suggest that hypermethylation of the caveolin-1 gene and an abnormal protein expression play a crucial role in cell differentiation, and in the phenotypical conversion of TCC into nonurothelial carcinomas. Promoter methylation of the hDAB2IP gene occurred more frequently in advanced muscle invasive (72.7%) than in superficial noninvasive (50%) TCC. DNA hypermethylation of p53 was detected in a quarter of the low-grade, low-stage TCC and undifferentiated small cell carcinomas, but only sporadically in squamous cell carcinomas, and was absent in high-grade, high-stage TCC. In conclusion, aberrant methylation and abnormal protein expression of the caveolin-1-gene is involved in the formation of nonurothelial carcinomas of the urinary bladder and promoter methylation of the hDAB2IP gene in the progression of TCC from a low to a high malignant potential.
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PMID:Transitional cell carcinomas and nonurothelial carcinomas of the urinary bladder differ in the promoter methylation status of the caveolin-1, hDAB2IP and p53 genes, but not in the global methylation of Alu elements. 1632 5

Tumor suppressor genes encode for proteins whose normal function is to inhibit cell transformation and whose inactivation is advantageous for tumor cell growth and survival. A variety of mechanisms result in the inactivation of tumor suppressor genes, including intragenic mutations, chromosomal deletions, and loss of expression by methylation-mediated transcriptional silencing or increased proteolysis. Tumor suppressor genes participate in a variety of critical and highly conserved cell functions, including regulation of the cell cycle and apoptosis, differentiation, surveillance of genomic integrity and repair of DNA errors, signal transduction, and cell adhesion. Tumor suppressor functions can be separated into 2 major categories: gatekeepers and caretakers. Gatekeepers directly inhibit tumor growth or promote tumor death. Inactivation of these genes contributes directly to cancer formation and progression. Among them, the p53 gene is the most well known. Located on chromosome band 17p13, p53 encodes a 53-kd multifunctional transcription factor that regulates the expression of genes involved in cell cycle control, apoptosis, DNA repair, and angiogenesis. In breast cancer, most studies have shown that p53 mutation or down-regulation is associated with adverse prognosis. Other tumor suppressor genes of interest in breast cancer include the retinoblastoma gene (pRb), PTEN, p16, nm23, and maspin.
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PMID:Tumor suppressor genes in breast cancer: the gatekeepers and the caretakers. 1646 15

Tumor suppressor gene inactivation as proposed by the Knudson model implies a sequential inactivation of two alleles of a gene. For example, the first allele is inactivated by a missense mutation, and the second one is inactivated by a deletion or insertion. The alteration of the p53 tumor suppressor gene is far to correspond only to this model. In the great majority of cancers, the mutated allele of p53 coexists with the normal allele. It is well known that the transcriptional activity is one of the most important functions of p53. The p53 protein is active as a tetramer (this complex activates the expression of targeted genes by binding to its consensus DNA sequence called the p53 response element). Experimental evidence shows that wild-type p53 interacts with mutant proteins to form heterotetramers. In association with wild-type proteins, mutant proteins drive the wild-type subunits into a mutant conformation. This association leads to a loss of trans-activating function. The capacity of mutant subunits to form heterotetramers with wild-type subunits and to commit them into a mutant conformation is called << dominant negative effect >>. Many p53 mutant proteins possess this dominant negative activity. Recently, several factors, which are implicated in the control of the dominant negative activity of p53 mutants, have been identified. The elucidation of these complex molecular functions, which are implicated in the dominant negative activity of the p53 mutated protein represents an important aspect in the comprehension of the biological mechanisms involved in carcinogenesis.
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PMID:[Dominant negative activity of mutated p53 proteins]. 1652 13

The clinical outcome for osteosarcoma (OS) remains discouraging despite efforts to optimize treatment using conventional modalities including surgery, radiotherapy and chemotherapy. Novel therapeutic approaches based on our expanding understanding of the mechanisms of tumor cell killing have the potential to alter this situation. Tumor suppressor gene therapy aims to restore the function of a tumor suppressor gene lost or functionally inactivated in cancer cells. One such molecule, the p53 tumor suppressor gene plays a critical role in safeguarding the integrity of the genome and preventing tumorigenesis. Introduction of wild-type (wt) p53 into transformed cells has been shown to be lethal for most cancer cells in vitro, but clinical trials of p53 gene replacement have had limited success. Analysis of these clinical trials highlighted the insufficient efficacy of current vectors and low proapoptotic activity of wt p53 as a single agent in vivo. In this review, a contemporary summarization of the current status of adenovirus-mediated p53 gene therapy of OS is presented. Advancement in our understanding of p53 tumor suppressor activity, the molecular biology of chemoresistant OS, and recent advances in tumor targeting with adenoviral vectors are also addressed. Based on these parameters, prospects for future investigations are proposed.
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PMID:Adenovirus-mediated p53 tumor suppressor gene therapy of osteosarcoma. 1675 79

Tumor suppressor function for Annexin A7 (ANXA7; 10q21) is based on cancer-prone phenotype in Anxa7(+/-) mouse and ANXA7 prognostic role in human cancers. Because ANXA7-caused liposome aggregation can be promoted by arachidonic acid (AA), we hypothesized that the phospholipid-binding tumor suppressor ANXA7 is associated with AA cascade. In a comparative study of ANXA7 versus canonical tumor suppressor p53 effects on AA lipoxygenation pathway in the p53-mutant and androgen-insensitive DU145 prostate cancer cells, both tumor suppressors altered gene expression of major 5-lipoxygenase (LOX) and 15-LOXs, including response to T helper 2 (Th2)-cytokine [interleukin-4 (IL-4)] and endogenous steroids (mimicked by dexamethasone). Wild-type and mutant ANXA7 distinctly affected expression of the dexamethasone-induced 15-LOX-2 (a prostate-specific endogenous tumor suppressor) as well as the IL-4-induced 15-LOX-1. On the other hand, wild-type p53 restored 5-LOX expression in DU145 to levels comparable to benign prostate epithelial cells. Using mass spectrometry of DNA affinity-enriched nuclear proteins, we detected different proteins that were bound to adjacent p53 and estrogen response elements in the 5-LOX promoter in DU145 cells introduced with ANXA7 versus p53. Sex hormone regulator 17-beta hydroxysteroid dehydrogenase 4 was identified under p53 introduction, which induced the 5-LOX expression. Meantime, nuclear proteins bound to the same 5-LOX promoter site under introduction of ANXA7 (that was associated with the repressed 5-LOX) were identified as zinc finger proteins ZNF433 and Aiolos, pyrin domain-containing NALP10, and the p53-regulating DNA repair enzyme APEX1. Thus, ANXA7 and p53 can distinctly regulate LOX transcription that is potentially relevant to the AA-mediated cell growth control in tumor suppression.
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PMID:Distinct effects of annexin A7 and p53 on arachidonate lipoxygenation in prostate cancer cells involve 5-lipoxygenase transcription. 1701 18


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