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 hepatitis B virus (HBV) correlates with the prevalence of hepatocellular carcinoma. It has recently been demonstrated that the complete viral genome very efficiently transforms the immortalized murine hepatocyte line FMH202 in vitro. Here it is shown that the viral transactivating protein X (HBx) is sufficient to transform FMH202 cells, albeit with lower efficiency. Clonal cell lines expressing HBx mRNA in moderate or high amounts grew in soft agar and formed tumours in nude mice. Growth efficiency in soft agar of HBx transformed cell lines was much lower than that of cell lines transformed with the complete genome, and latency of tumour induction in nude mice was significantly longer after inoculation of HBx than of HBV transformed FMH202 cell lines. A marker of complete transformation, p53, was found to be phosphorylated more strongly in HBx transfected cell lines than in controls, and a cellular kinase was found to be associated with p53 complexes from HBx transformed cell lines. p53 was of wild-type conformation and was located in the nucleus of transformed cells.
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PMID:Properties of tumour suppressor p53 in murine hepatocyte lines transformed by hepatitis B virus X protein. 956 72

Human papillomaviruses (HPV) infect mucosal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. Persistent infection with sexually transmitted oncogenic HPV types represents the major risk factor for the development of cervical cancer. The development of HPV-associated cervical cancer has been closely linked to the expression of the viral oncogenes E6 and E7 in the tumor cells. The major viral oncoproteins, E6 and E7, target the cellular tumor suppressor gene products p53 and Rb, respectively. As detailed within, these interactions result in the stimulation of proliferation and the inhibition of apoptosis, thus representing major oncogenic insults to the infected cell. In addition to mediating transformation, the E6 and E7 genes also play significant roles in altering the immune response against infected cells by suppressing interferon (IFN) expression and signaling. At the clinical level, IFNs have been used in the treatment of HPV-associated cervical intraepithelial neoplasia (CIN) or cervical cancers with mixed results. The success of the treatment is largely dependent on the subtype of HPV and the immune response of the patients. Despite this inefficiency, the increasing knowledge about the regulation of IFN signaling pathways at molecular level may hold a promise for the use of new therapeutic strategies against HPV infection. Studies on the regulation of the function of IFN-inducible gene products by the E6 and E7 may lead to the development of new therapeutic approaches based on strategies that modify the function of the HPV oncoproteins and restore IFN-signaling pathways through endogenous control mechanisms.
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PMID:Control of interferon signaling in human papillomavirus infection. 1132 99

Persistent infection with oncogenic human papillomaviruses (HPVs) is the most important factor in the induction of uterine cervical cancer, a leading cause of cancer mortality in women worldwide. Upon cell transformation, continual expression of the viral oncogenes is required to maintain the transformed phenotype. The viral E6 protein forms a ternary complex with the cellular E6-AP protein and p53 protein which promotes the rapid degradation of p53. Recent studies have revealed that lignans from the creosote bush (3'-O-methyl-nordihydroguaiaretic acid) can repress the viral promoter responsible for E6 gene expression. Work reported here shows that the lignan can subvert viral oncogene function resulting in stabilized p53 protein within treated HPV-containing tumor cells. The stabilized p53 is transcriptionally active as demonstrated by a luciferase reporter vector and induction of genes for Bax and PUMA proteins. Apoptosis is detected by annexin V binding to treated cells as analyzed by flow cytometry. Programmed cell death is confirmed by the induction of active caspases and TUNEL assay. Initiator caspase-9 is activated first, followed later by the effector caspase-3 enzyme. The stabilization and induced apoptosis are not observed within treated HPV-negative cervical tumor cells. Quantitative real time RT-PCR analysis of endogenous E6 gene transcription from the integrated HPV 16 promoter shows at least a fivefold repression of expression as compared to untreated cells. These results indicate that the loss of E6 protein in treated cells could be, in part, responsible for the stabilization of p53 within the lignan treated cells.
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PMID:A plant lignan, 3'-O-methyl-nordihydroguaiaretic acid, suppresses papillomavirus E6 protein function, stabilizes p53 protein, and induces apoptosis in cervical tumor cells. 1739 35

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

Persistent infection with high risk human papillomavirus is a necessary risk factor in the etiology of invasive cervical carcinoma. With regard to molecular details, the best studied types are HPV16 and HPV18 which are found in 70% of cervical cancer worldwide, however factors associated with the progression of individual cervical intraepithelial neoplasias into cancer are still poorly understood. Intratype amino acid variations in the immortalizing and transforming early proteins E6 and E7 were described to be associated with progressive disease and linked to increased viral persistence or progression. One of the key actions of high risk HPVE6 proteins is the inhibition of the function of p53, a tumor suppressor protein, by enhancing its degradation through the ubiquitin pathway. In this study, variants of five HPV type E6 proteins (HPV35, 53, 56, 66, and 70) isolated from patient materials are described and functional analysis of them were done with respect to p53 degradation. Interestingly the E6 protein of HPV type 53, which has no consistent risk classification in the literature showed the highest variability in our study. The analysis of all variants revealed no differences with regard to the degradation ability for p53 compared to the prototype E6 proteins, suggesting that the variants tested revealed no altered functions related to the carcinogenicity of the respective HPV types. It therefore seems more likely that variations in the E6 gene sequence may allow evasion from the hosts immune system, supporting increased viral persistence.
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PMID:Isolation and functional analysis of five HPVE6 variants with respect to p53 degradation. 1820 17

We contrast the efforts to treat ovarian cancer and cervical cancer through vaccination because of their different pathobiology. A plethora of approaches have been developed for therapeutic vaccination against cancer, many of which target defined tumor-associated antigens (TAAs). Persistent infection with oncogenic human papillomavirus (HPV) types causes cervical cancer. Furthermore, cervical cancer patients frequently mount both humoral and T-cell immune responses to the HPV E6 and E7 oncoproteins, whose expression is required for the transformed phenotype. Numerous vaccine studies target these viral TAAs, including recent trials that may enhance clearance of pre-malignant disease. By contrast, little is known about the etiology of epithelial ovarian cancer. Although it is clear that p53 mutation or loss is a critical early event in the development of epithelial ovarian cancer, no precursor lesion has been described for the most common serous histotype, and even the location of its origin is debated. These issues have complicated the selection of appropriate ovarian TAAs and the design of vaccines. Here we focus on mesothelin as a promising ovarian TAA, because it is overexpressed and immunogenic at high frequency in patients, is displayed on the cell surface, and potentially contributes to ovarian cancer biology.
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PMID:Antigen-specific immunotherapy of cervical and ovarian cancer. 1836 94

Persistent infection with hepatitis C virus (HCV) induces tumorigenicity in hepatocytes. To gain insight into the mechanisms underlying this process, we generated monoclonal antibodies on a genome-wide scale against an HCV-expressing human hepatoblastoma-derived cell line, RzM6-LC, showing augmented tumorigenicity. We identified 3beta-hydroxysterol Delta24-reductase (DHCR24) from this screen and showed that its expression reflected tumorigenicity. HCV induced the DHCR24 overexpression in human hepatocytes. Ectopic or HCV-induced DHCR24 overexpression resulted in resistance to oxidative stress-induced apoptosis and suppressed p53 activity. DHCR24 overexpression in these cells paralleled the increased interaction between p53 and MDM2 (also known as HDM2), a p53-specific E3 ubiquitin ligase, in the cytoplasm. Persistent DHCR24 overexpression did not alter the phosphorylation status of p53 but resulted in decreased acetylation of p53 at lysine residues 373 and 382 in the nucleus after treatment with hydrogen peroxide. Taken together, these results suggest that DHCR24 is elevated in response to HCV infection and inhibits the p53 stress response by stimulating the accumulation of the MDM2-p53 complex in the cytoplasm and by inhibiting the acetylation of p53 in the nucleus.
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PMID:Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase. 1986 17

Persistent infection with high-risk human papillomaviruses (HPVs), especially type 16 has been undeniably linked to cervical cancer. The Asian-American (AA) variant of HPV16 is more common in the Americas than the prototype in cervical cancer. The different prevalence is based on three amino acid changes within the E6 protein denoted Q14H/H78Y/L83V. To investigate the mechanism(s) behind this observation, both E6 proteins, in the presence of E7, were evaluated for their ability to extend the life span of and transform primary human foreskin keratinocytes (PHFKs). Long-term cell culture studies resulted in death at passage 9 of vector-transduced PHFKs (negative control), but survival of both E6 PHFKs to passage 65 (and beyond). Compared with E6/E7 PHFKs, AA/E7 PHFKs were significantly faster dividing, developed larger cells in monolayer cultures, showed double the epithelial thickness and expressed cytokeratin 10 when grown as organotypic raft cultures. Telomerase activation and p53 inactivation, two hallmarks of immortalization, were not significantly different between the two populations. Both were resistant to anoikis at later passages, but only AA/E7 PHFKs acquired the capacity for in vitro transformation. Proteomic analysis revealed markedly different protein patterns between E6/E7 and AA/E7, particularly with respect to key cellular metabolic enzymes. Our results provide new insights into the reasons underlying the greater prevalence of the AA variant in cervical cancer as evidenced by characteristics associated with higher oncogenic potential.
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PMID:The immortalizing and transforming ability of two common human papillomavirus 16 E6 variants with different prevalences in cervical cancer. 2038 92

Cervical cancer remains unique among solid tumor malignancies. Persistent infection with oncogenic subtypes of the human papillomavirus (HPV) results in carcinogenesis, predominantly occurring at the cervical transformation zone where endocervical columnar cells undergo metaplasia to a stratified squamous epithelium. The molecular cascade involving viral oncoproteins, E6 and E7 and their degradative interactions with cellular tumor suppressor gene products, p53 and pRb, respectively, has been precisely delineated. The precursor state of cervical neoplasia may last for years allowing for ready detection through successful screening programs in developed countries using cervical cytology and/or high-risk HPV DNA testing. Prophylactic HPV L1 capsid protein vaccines using virus-like-particle technology have been developed to prevent primary infection by the most common high-risk HPVs (16 and 18). Women who lack access to health care and those who undergo sporadic screening remain at risk. Although radical surgery (including fertility-sparing surgery) is available for patients with early-stage cancers, and chemoradiation plus high-dose-rate brachytherapy can cure the majority of those with locally advanced disease, patients with metastatic and nonoperable recurrent cervical cancer constitute a high-risk population with an unmet clinical need. On August 14, 2014, the FDA approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer. This review will highlight advances in translational science, antiangiogenesis therapy and immunotherapy for advanced disease.
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PMID:New strategies in advanced cervical cancer: from angiogenesis blockade to immunotherapy. 2510 84

Persistent infection with high-risk human papillomaviruses is the main etiological factor in cervical cancer (CC). The human papillomavirus type 16 (HPV16) E7 oncoprotein alters several cellular processes, regulating the expression of many genes in order to avoid cell cycle control. Retinoic acid receptor beta (RARB) blocks cell growth, inducing differentiation and apoptosis. This tumor suppressor gene is gradually silenced in late passages of foreskin keratinocytes immortalized with HPV16 and in various tumors, including CC, mainly by epigenetic modifications. We investigated the effect of E7 oncoprotein on RARB gene expression. We found that HPV16 E7 increases RARB mRNA and RAR-beta protein expression both in vitro and in the cervix of young K14E7 transgenic mice. In E7-expressing cells, RARB overexpression is further increased in the presence of the tumor suppressor p53 (TP53) R273C mutant. This effect does not change when either C33-A or E7-expressing C33-A cell line is treated with Trichostatin A, suggesting that E7 enhances RARB expression independently of histone deacetylases inhibition. These findings indicate that RARB overexpression is part of the early molecular events induced by the E7 oncoprotein.
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PMID:Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice. 2617 16


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