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)

Persistent infection by high-risk types of human papillomaviruses (HPV) is a necessary cause of cervical cancer, with HPV16 the most prevalent, accounting for more than 50% of reported cases. The virus encodes the E6 and E7 oncoproteins, whose expression is essential for maintenance of the malignant phenotype. To select efficacious siRNAs applicable to RNAi therapy for patients with HPV16+ cervical cancer, E6 and E7 siRNAs were designed using siDirect computer software, after which 10 compatible with all HPV16 variants were selected, and then extensively examined for RNAi activity and specificity using HPV16+ and HPV16-cells. Three siRNAs with the highest RNAi activities toward E6 and E7 expression, as well as specific and potent growth suppression of HPV16+ cancer cells as low as 1 nM were chosen. Growth suppression was accompanied by accumulation of p53 and p21(WAF1/CIP1), as well as morphological and cytochemical changes characteristic of cellular senescence. Antitumor activity of one of the selected siRNAs was confirmed by retarded tumor growth of HPV16+ cells in NOD/SCID mice when locally injected in a complex with atelocollagen. Our results demonstrate that these E6 and E7 siRNAs are promising therapeutic agents for treatment of virus-related cancer.
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PMID:New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer. 1815 44

Previous study reported that the activation of Ras pathway cooperated with E6/E7-mediated inactivation of p53/pRb to transform immortalized normal human astrocytes (NHA/hTERT) into intracranial tumors strongly resembling human astrocytomas. The mechanism of how H-Ras contributes to astrocytoma formation is unclear. Using genetically modified NHA cells (E6/E7/hTERT and E6/E7/hTERT/Ras cells) as models, we investigated the mechanism of Ras-induced tumorigenesis. The overexpression of constitutively active H-RasV12 in E6/E7/hTERT cells robustly increased the levels of urokinase plasminogen activator (uPA) mRNA, protein, activity and invasive capacity of the E6/E7/hTERT/Ras cells. However, the expressions of MMP-9 and MMP-2 did not significantly change in the E6/E7/hTERT and E6/E7/hTERT/Ras cells. Furthermore, E6/E7/hTERT/Ras cells also displayed higher level of uPA activity and were more invasive than E6/E7/hTERT cells in 3D culture, and formed an intracranial tumor mass in a NOD-SCID mouse model. uPA specific inhibitor (B428) and uPA neutralizing antibody decreased uPA activity and invasion in E6/E7/hTERT/Ras cells. uPA-deficient U-1242 glioblastoma cells were less invasive in vitro and exhibited reduced tumor growth and infiltration into normal brain in xenograft mouse model. Inhibitors of Ras (FTA), Raf (Bay 54-9085) and MEK (UO126), but not of phosphatidylinositol 3-kinase (PI3K) (LY294002) and of protein kinase C (BIM) pathways, inhibited uPA activity and cell invasion. Our results suggest that H-Ras increased uPA expression and activity via the Ras/Raf/MEK signaling pathway leading to enhanced cell invasion and this may contribute to increased invasive growth properties of astrocytomas.
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PMID:H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway. 1838 43

Ten novel human pancreatic carcinoma cell lines (Sui65 through Sui74) were established from a transplantable pancreatic carcinoma cell line. All the cell lines resembled the original clinical carcinoma in terms of the morphological and biological features, presenting with genetic alterations such as point mutations of K-ras and p53, attenuation or lack of SMAD4 and p16 and other relevant cellular characteristics. Using this panel, we evaluated the effects of 5-FU in suppressing the proliferation of pancreatic carcinoma cells. When tested in vitro, although Sui72 was highly susceptible to 5-FU, the other cell lines were found to be resistant to the drug. When Sui72 and Sui70 were implanted subcutaneously in SCID mice followed by treatment with 5-FU, the drug was found to be effective against Sui72 but not Sui70, consistent with the results in vitro. In order to identify the molecular determinant for high sensitivity of Sui72 to 5-FU, we examined the mRNA expression levels of the metabolic enzymes of 5-FU. Decreased expression of DPYD was observed in Sui72 as compared with other cell lines (0.1 versus 0.6 +/- 0.5, 0.1-fold). It is believed that the novel cell lines established in the present study will be useful for analyzing the pattern of progression of pancreatic cancer and for evaluating the efficacy of anticancer agents.
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PMID:Establishment and molecular profiling of a novel human pancreatic cancer panel for 5-FU. 1869 40

Morphology and function of human organs and tissues are well maintained in the improved SCID (severe combined immunodeficient) mice for a long period (approximately 3 years). To study the radiation-induced damage on human thyroid gland, human thyroid tissues transplanted to SCID mice were consecutively exposed to X-rays or 137Cs gamma-rays at high and low dose rates for approximately 2 years. Consecutive irradiation resulted in the disappearance of follicles and significant decrease of thyroid hormone secretion. Mutations in p53 and c-kit genes were induced significantly in human thyroid tissues from old head and neck cancer patients (av. 56.8 years, 4 males) and a Graves' disease patient (20 years, male) over the dose of 24 Gy (44.7+/-5.9 Gy, mean+/-S.E) and 11 Gy (20.2+/-7.8 Gy), respectively, while mutations were not detected at lower doses nor in unexposed matched controls (p < 0.01). There were significant differences in mutation frequency in the transplanted human thyroid tissues (31 years, female) between high dose rate (1.19 Gy/min; 8 in 20 tissues) and low dose rate (0.00023 Gy/min; 0 in 14 tissues) exposures (p < 0.01). Mutations were not detected in RET, K-ras and beta-catenin genes. Expression analysis by GeneChip indicated that gene expression was also well maintained in the transplanted human thyroid tissues. However, lower doses (1 or 3 Gy) of 137Cs gamma-rays can induce changes in gene expression in the transplanted human thyroid tissues. Furthermore, fatally irradiated SCID mice could survive with human bone marrow cell transplantation. When about half of mouse bone marrows were replaced by human bone marrow cells, the human bone marrow cells showed high sensitivity to gamma-irradiation; 28.0% and 0.45% survival after 0.5 and 2.0 Gy exposures, respectively.
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PMID:Differential radiation sensitivity to morphological, functional and molecular changes of human thyroid tissues and bone marrow cells maintained in SCID mice. 1877 92

Increasing evidence on cancer stem cells suggest that stem cells are susceptive to carcinogenesis and consequently can be the origin of many cancers. We have recently established a telomerase-transduced human mesenchymal stem cell line and subsequently irradiated this in order to achieve malignant transformation. In the present study, we analyzed the long-term effect of ionizing radiation on these cells and investigate whether radiation can trigger tumor development. The cells were irradiated with a low (2.5 Gy) and a high (15 Gy) dose of gamma-rays and followed for up to 6 months after radiation. A subclone of the cells irradiated with 2.5 Gy of gamma-rays formed tumors after implantation to severe combined immunodeficiency mice. During the process of transformation, the cells showed accelerated telomere shortening, increased levels of anaphase bridges and a shift from balanced to unbalanced translocations. The tumor suppressor genes p53 and p21(CIP1) functioned normally throughout the study. Our observations indicate that radiation destabilized the telomeres and that the presence of uncapped telomeres initiated fusion-break-fusion cycles, resulting in increased chromosomal instability and tumor formation. Thus, bone marrow-derived human mesenchymal stem cells are capable of exhibiting a malignant phenotype.
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PMID:Transformation of human mesenchymal stem cells in radiation carcinogenesis: long-term effect of ionizing radiation. 1894 8

Incidence of nasopharyngeal carcinoma (NPC) remains high in endemic regions. Prevention of tumor recurrences and metastases is a crucial approach to improve therapeutic outcome in NPC patients. In this study, we investigated the effects of the cotransfer of the tumor suppressor gene, p53, in combination with the immunostimulatory genes, GM-CSF and B7-1, on tumor regression and subsequent tumor recurrence. We constructed a recombinant adenovirus carrying human wild-type p53, granulocyte-macrophage colony-stimulating factor (GM-CSF), and B7-1 genes (Ad-p53/GM-CSF/B7-1), which mediated high-level expression of these three genes in NPC CNE-1 cells. Ad-p53/GM-CSF/B7-1 infection inhibited the growth of CNE-1 cells and induced tumor-specific cytotoxic T-lymphocytes (CTLs) in vitro. In CNE-1 xenograft tumor models in huPBL-nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, an intratumoral injection of Ad-p53/GM-CSF/B7-1 resulted in a reduced tumor burden, compared to normal saline (NS) and Ad-p53 controls. Tumors in the Ad-p53/GM-CSF/B7-1 group displayed diffuse necrosis and infiltration of human T-cells. Further, the tumor occurrence of CNE-1 cell rechallenge largely decreased after the primary tumor was intratumorally injected with Ad-p53/GM-CSF/B7-1 in the HuPBL-NOD/SCID mice model. Only 2 of 8 (25%) animals in the Ad-p53/GM-CSF/B7-1 group had developed measurable tumors, which demonstrated extensive necrosis and much more human T-cell infiltration, compared to 5 of 7 (71%) in the NS and Ad-p53 groups. Therefore, the adenovirus-mediated introduction of p53, GM-CSF, and B7-1 genes could improve local control and prevent the recurrence or metastases of NPC tumors, which suggests a potential therapeutic value in NPC treatment.
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PMID:Gene therapy for human nasopharyngeal carcinoma by adenovirus-mediated transfer of human p53, GM-CSF, and B7-1 genes in a mouse xenograft tumor model. 1899 31

For future cell-based therapies for liver diseases, the shortage of cell sources must be resolved. Immortalized human hepatocytes are expected to be among the new sources. In addition to telomerase activation by the introduction of human telomerase reverse transcriptase (hTERT), inactivation of the p16/RB pathway and/ or p53 by E6/E7 of human papillomavirus type 16 (HPV16) has been shown to be useful for efficient immortalization of several human cell types. Here we report the immortalization of human hepatocytes by the introduction of HPV16 E6/E7 and hTERT. Human adult hepatocytes were lentivirally transduced with HPV16 E6/E7 and hTERT. Two human immortalized hepatocyte cell lines were established and were named HHE6E7T-1 and HHE6E7T-2. Those cells proliferated in culture beyond 200 population doublings (PDs). Albumin synthesis and expression of liver-enriched genes were confirmed, but gradually decreased as passages progressed. Karyotype analysis showed that HHE6E7T-1 cells remained near diploid but that HHE6E7T-2 cells showed severe aneuploidy at 150 PDs. Subcutaneous injection of these cells into severe combined immunodeficiency (SCID) mice did not induce tumor development. Intrasplenic transplantation of dedifferentiated HHE6E7T-1 cells over 200 PDs significantly improved the survival of acetaminophen-induced acute liver failure SCID mice. In conclusion, we successfully established immortalized human hepatocytes that retain the characteristics of differentiated hepatocytes. We also showed the reduction of hepatocyte-specific functions in long-term culture. However, the results of intrasplenic transplantation to SCID mice with acetaminophen-induced acute liver failure showed the possibility of HHE6E7T-1 serving as a cell source for hepatocyte transplantation.
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PMID:Establishment of immortalized human hepatocytes by introduction of HPV16 E6/E7 and hTERT as cell sources for liver cell-based therapy. 1917 44

Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and is a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML progenitor cells.
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PMID:Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. 1945 29

Much attention has been paid to gene therapy since 1990's. No remarkable success has been achieved and several serious adverse effects such as leukemia in X-SCID gene therapy have been reported. Nevertheless, trials to treat hereditary disease, cancers and cardiovascular disease using therapeutic gene-loaded vectors are continuously being performed. Recently, some gene drugs such as p53-loaded adenovirus vector, oncolytic adenovirus and HGF plasmid DNA are produced and remain to be commercially available. Stem cell-based gene therapy will be main focus in hereditary disease gene therapy. In cancer gene therapy, regulation of anti-tumor immunity and improvement of gene-modified oncolytic virus will be more fully investigated.
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PMID:[Progress of human gene therapy]. 1950 11

Overexpression of BMI1 correlates with cancer development, progression, and therapy failure; however, the underlying molecular mechanisms remain to be fully elucidated. Using the C666-1 nasopharyngeal cancer (NPC) model, the role of BMI1 in mediating response of NPC cells to radiation therapy (RT) was investigated. The results showed a novel radioresistance function for BMI1 in NPC, wherein BMI1 depletion sensitized NPC cells to RT. Cell cycle analysis and transmission electron microscopy (TEM) showed apoptosis as the major mode of cell death, and the mitochondria as a primary targeted cellular organelle. Genome-wide microarray and pathway analyses revealed that the P53 pathway is a critical mediator of this process. Cotransfection with siP53 rescued C666-1 cells from cytotoxicity upon BMI1 depletion and RT, thereby corroborating the role for P53. Pretreatment with the antioxidant, Trolox, inhibited apoptosis, indicating that production of reactive oxygen species (ROS) is also mediating cytotoxicity. In vivo, BMI1 depletion combined with RT abrogated tumor-forming capacity in SCID mice, showing the relevance of this process in a more complex tumor environment. Hence, we show a novel role for BMI1 in conferring radioresistance in cancer cells through the downregulation of p53-mediated apoptosis. These results suggest a potential strategy of BMI1 depletion combined with RT for tumors wherein BMI1 appears to be driving disease progression.
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PMID:Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy. 1957 17


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