Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While both in vivo and in vitro evidence has suggested that liver cells undergo apoptosis in response to dengue virus infection, little is known about the mechanism of induction. Given that the p53 tumour suppressor gene is a key mediator of apoptosis, we sought to define the role of this gene in response to dengue virus infection. After infection, a p53 wild type liver cell line (HepG2) showed changes consistent with apoptosis including alterations of cell morphology, cellular detachment and DNA laddering. However, p53 was neither up-regulated, nor showed any evidence of complexing with dengue virus proteins as determined by immunoprecipitation. Infection of a p53 null liver cell line (Hep3B) also produced changes consistent with the induction of apoptosis. While the profile of the cells undergoing apoptosis in each cell line was similar as determined by flow cytometry, the absolute levels were markedly different with up to 90% of Hep3B cells undergoing apoptosis compared to only 20% of HepG2 cells at day 5 post infection. By day 7, all Hep3B infected cells were dead. In contrast, it proved possible to culture dengue virus infected HepG2 cells for 3 months. Viral progeny released from the p53 null cell line were nine-fold higher per attached cell than from the p53 wild type cell line. These results suggest that, while induction of apoptosis in liver cells is mediated by a non-p53 regulated pathway, p53 may play a role in restricting the level of viral progeny to below a critical level at which apoptosis is triggered.
 ...
PMID:Apoptosis in dengue virus infected liver cell lines HepG2 and Hep3B. 1474 67

The nucleolus is a dynamic subnuclear structure involved in ribosome subunit biogenesis, cell cycle control and mediating responses to cell stress, among other functions. While many different viruses target proteins to the nucleolus and recruit nucleolar proteins to facilitate virus replication, the effect of infection on the nucleolus in terms of morphology and protein content is unknown. Previously we have shown that the coronavirus nucleocapsid protein will localize to the nucleolus. In this study, using the avian infectious bronchitis coronavirus, we have shown that virus infection results in a number of changes to the nucleolus both in terms of gross morphology and protein content. Using confocal microscopy coupled with fluorescent labelled nucleolar marker proteins we observed changes in the morphology of the nucleolus including an enlarged fibrillar centre. We found that the tumour suppressor protein, p53, which localizes normally to the nucleus and nucleolus, was redistributed predominately to the cytoplasm.
 ...
PMID:Changes in nucleolar morphology and proteins during infection with the coronavirus infectious bronchitis virus. 1681 67

Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necro-inflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF- alpha) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes. Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis. Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC) in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with suppression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker's syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache, fullness in the head, dizziness, lethargy, prickling sensation, pruritus and arthralgia.
 ...
PMID:Heavy smoking and liver. 1703 78

An increasing number of tumour suppressor genes are induced by interferons (IFNs) and may play an important role in the control of cell proliferation induced by this cytokine. In addition, pathways triggered by both tumour suppressors and IFN converge as common targets for non-related tumour viruses. The inhibition of the IFN response by animal viruses is explained by the fundamental role that IFN plays to control virus infection. However, the reasons why many viruses, including those that do not require the replication of the host, target tumour suppressor pathways are varied and are still under investigation. Here we review those findings that support that tumour suppressors may have a role in the control of virus infection.
 ...
PMID:Control of virus infection by tumour suppressors. 1734 39

Nasopharyngeal carcinoma (NPC) is a prevalent tumour in southern China and southeast Asia, particularly in the Cantonese population, where its incidence has remained high for decades. Recent studies have demonstrated that the aetiology of NPC is complex, involving multiple factors including genetic susceptibility, infection with the Epstein-Barr virus (EBV) and exposure to chemical carcinogens. During development of the disease, viral infection and multiple somatic genetic and epigenetic changes synergistically disrupt normal cell function, thus contributing to NPC pathogenesis. NPC is highly radiosensitive and chemosensitive, but treatment of patients with locoregionally advanced disease remains problematic. New biomarkers for NPC, including EBV DNA copy number or methylation of multiple tumour suppressor genes, which can be detected in serum and nasopharyngeal brushings, have been developed for the molecular diagnosis of this tumour. Meanwhile, new therapeutic strategies such as intensity-modulated radiation therapy and immuno- and epigenetic therapies might lead to more specific and effective treatments.
 ...
PMID:Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments. 1747 89

The human cytomegalovirus (HCMV) has been proposed to complete its final envelopment on cytoplasmic membranes prior to its release to the extracellular medium. The nature of these membranes and the mechanisms involved in virus envelopment and release are poorly understood. Here we show by immunogold-labelling and electron microscopy that CD63, a marker of multivesicular bodies (MVBs), is incorporated into the viral envelope, supporting the notion that HCMV uses endocytic membranes for its envelopment. We therefore investigated a possible role for the cellular endosomal sorting complex required for transport (ESCRT) machinery in HCMV envelopment. Depletion of tumour suppressor gene 101 and ALIX/AIP1 with small interfering RNAs (siRNAs) in HCMV-infected cells did not affect virus production. In contrast, siRNAs against the vacuolar protein sorting 4 (VPS4) proteins silenced the expression of VPS4A and VPS4B, inhibited the sorting of epidermal growth factor to lysosomes, the formation of HIV Gag-derived virus-like particles and vesicular stomatitis virus infection, but enhanced the number of HCMV viral particles produced. Treatment of infected cells with protease inhibitors also increased viral production. These studies indicate that, in contrast to some enveloped RNA viruses, HCMV does not require the cellular ESCRT machinery to complete its envelopment.
 ...
PMID:The ESCRT machinery is not required for human cytomegalovirus envelopment. 1776 Aug 79

On detecting viral RNAs, the RNA helicase retinoic acid-inducible gene I (RIG-I) activates the interferon regulatory factor 3 (IRF3) signalling pathway to induce type I interferon (IFN) gene transcription. How this antiviral signalling pathway might be negatively regulated is poorly understood. Microarray and bioinformatic analysis indicated that the expression of RIG-I and that of the tumour suppressor CYLD (cylindromatosis), a deubiquitinating enzyme that removes Lys 63-linked polyubiquitin chains, are closely correlated, suggesting a functional association between the two molecules. Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response. CYLD removes polyubiquitin chains from RIG-I as well as from TANK binding kinase 1 (TBK1), the kinase that phosphorylates IRF3, coincident with an inhibition of the IRF3 signalling pathway. Furthermore, CYLD protein level is reduced in the presence of tumour necrosis factor and viral infection, concomitant with enhanced IFN production. These findings show that CYLD is a negative regulator of RIG-I-mediated innate antiviral response.
 ...
PMID:The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. 1863 86

The human papillomavirus (HPV) E6 and E7 oncogenes have direct effects on host cell proliferation. The viral E2 protein regulates transcription of E6 and E7 and thereby has an indirect effect on cell proliferation. In HPV-induced tumours, misappropriate random integration of the viral genome into the host chromosome often leads to disruption of the E2 gene and the loss of E2 expression. This results in cessation of the virus life cycle and the deregulation of E6 and E7 and is an important step in tumourigenesis. However, prior to these integration events, E2 can interact directly with the E6 and E7 proteins and modulate their activities. E2 also interacts with a variety of host proteins, including the p53 tumour suppressor protein. Here we outline evidence that suggests a role for E2 in the regulation of cell proliferation, and we discuss the importance of this regulation in viral infection and cervical tumourigenesis.
 ...
PMID:The regulation of cell proliferation by the papillomavirus early proteins. 1918 49

The interferon regulated transcription factor IRF-1 is a tumour suppressor protein that is activated in response to viral infection and cell signalling activated by double stranded DNA lesions. IRF-1 has a short half-life (t(0.5) 20-40 min) allowing rapid changes in steady state levels by modulating its rate of degradation and/or synthesis. However, little is known about the pathway(s) leading to IRF-1 protein degradation or what determines the rate of degradation in cells. Here we establish a role for discrete motifs in the enhancer domain of IRF-1 in directing polyubiquitination and degradation. By studying the structure of the enhancer domain as related to its role in the turnover of IRF-1 we have demonstrated that this region is not subject to modification by ubiquitin but rather that it contains both an ubiquitination signal and a distinct degradation signal. Removal of the C-terminal 70 amino acids from IRF-1 inhibits both its degradation and polyubiquitination, whereas removal of the C-terminal 25 amino acids inhibits degradation of the protein but does not prevent its ubiquitination. Furthermore, consistent with the C-terminus being involved in targeting or recognition by an E3-ligase or associated protein(s) the enhancer domain can act in trans to inhibit IRF-1 ubiquitination by endogenous E3-ligase activity. The identification of structural determinants that signals IRF-1 polyubiquitination and which can be uncoupled from IRF-1 degradation lends support to the idea that the degradation of selective substrates can be regulated at multiple steps in the ubiquitin-proteasome system.
 ...
PMID:Role of the IRF-1 enhancer domain in signalling polyubiquitination and degradation. 1945 Jun 80

Penile verrucous carcinoma is a rare disease and little is known of its aetiology or pathogenesis. In this study we examined cell-cycle proteins expression and correlation with human papillomavirus infection in a series of 15 pure penile verrucous carcinomas from a single centre. Of 148 penile tumours, 15 (10%) were diagnosed as pure verrucous carcinomas. The expression of the cell-cycle-associated proteins p53, p21, RB, p16(INK4A) and Ki67 were examined by immunohistochemistry. Human papillomavirus infection was determined by polymerase chain reaction to identify a wide range of virus types. The expression of p16(INK4A) and Ki67 was significantly lower in verrucous carcinoma than in usual type squamous cell carcinoma, whereas the expression of p53, p21 and RB was not significantly different. p53 showed basal expression in contrast to usual type squamous cell carcinoma. Human papillomavirus infection was present in only 3 out of 13 verrucous carcinomas. Unique low-risk, high-risk and mixed viral infections were observed in each of the three cases. In conclusion, lower levels of p16(INK4A) and Ki67 expressions differentiate penile verrucous carcinoma from usual type squamous cell carcinoma. The low Ki67 index reflects the slow-growing nature of verrucous tumours. The low level of p16(INK4A) expression and human papillomavirus detection suggests that penile verrucous carcinoma pathogenesis is unrelated to human papillomavirus infection and the oncogenes and tumour suppressor genes classically altered by virus infection.
 ...
PMID:HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis. 1946 1


<< Previous 1 2 3 Next >>