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)

The resistance of cancers to conventional therapies has inspired the search for novel strategies. One such approach, namely gene therapy, is based upon the introduction of genes such as those encoding suicide proteins, tumour suppressor proteins or cytokines into tumour cells by means of a genetic vector. The efficiency with which viruses transfer their genes from one host cell to another has led to the widespread use of viruses as genetic vectors. For safety reasons, such virus vectors are generally replication-defective but, unfortunately, this has limited the efficacy of treatment by restricting the number of cells to which the therapeutic gene is delivered. For this reason, the use of replication-competent viruses has been proposed, since virus replication would be expected to lead to amplification and spread of the therapeutic genes in vivo. The replication of many viruses results in lysis of the host cells. This inherent cytotoxicity, together with the efficiency with which viruses can spread from one cell to another, has inspired the notion that replication-competent viruses could be exploited for cancer treatment. Some viruses have been shown to replicate more efficiently in transformed cells but it is unlikely that such examples will exhibit a high enough degree of tumour selectivity, and hence safety, for the treatment of patients. Our increasing knowledge of the pathogenesis of virus disease and the ability to manipulate specific regions of viral genomes have allowed the construction of viruses that are attenuated in normal cells but retain their ability to lyse tumour cells. Such manipulations have included modifying the ability of viruses to bind to, or replicate in, particular cell types, while others have involved the construction of replication-competent viruses encoding suicide proteins or cytokines. Naturally occurring or genetically engineered oncolytic viruses based upon adenovirus, herpes simplex virus, Newcastle disease virus, poliovirus, vesicular stomatitis virus, weasles virus and reovirus have been described. The results of animal studies are encouraging and a number of viruses are now being evaluated in clinical trials.
J Gen Virol 2002 Mar
PMID:Cytolytic viruses as potential anti-cancer agents. 1184 43

Laryngeal papillomas are caused by infection of the laryngeal epithelium by human papillomavirus type 6 or type 11 (HPV-6/-11). Previous studies in our laboratory have demonstrated an increase in PI3 kinase levels in papilloma tissue. However, activation of the downstream effector of PI3 kinase, protein kinase B (PKB/Akt), was reduced. This observation was explained by the elevated expression of the phosphatase and tensin homologue (PTEN), a recently characterized tumour suppressor, in papilloma tissue. Recent investigation of the possible functional roles of PTEN during papilloma development has now indicated that the level of tyrosine(705)-phosphorylated signal transducer and activator of transcription 3 [PTyr(705)STAT3] could be inversely correlated to that of PTEN as well. In vitro phosphatase assays suggested the presence of an increased level of a PTyr(705)STAT3 phosphatase in papilloma extract. Immunodepletion of PTEN from papilloma extracts resulted in a reduction of the PTyr(705)STAT3 phosphatase activity. Transfection of PTEN cDNA into HeLa cells attenuated STAT3 phosphorylation at Tyr(705) in a dose-dependent manner. This attenuation of STAT3 phosphorylation was independent of the STAT3 kinase. Interestingly, introduction of a lipid phosphatase mutant of PTEN (G129E) resulted in heightened PTyr(705)STAT3 phosphatase activity, relative to that obtained from wild-type PTEN transfection. These data indicate that PTEN negatively regulates STAT3 activation in HPV-infected papilloma cells. Induction of PTEN and reduction of activated STAT3 might be a result of a host defence mechanism or a virus-directed strategy to alter normal epithelial differentiation programming.
J Gen Virol 2002 Jul
PMID:PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells. 1207 83

The E1 region of adenovirus (Ad) type 5 is capable of transforming cells. According to current concepts, the Ad E1B 55 kDa (E1B 55K) protein enables transformed cells to grow by constantly binding and inactivating the p53 tumour suppressor protein. To test this model, the transcriptional activity of p53 was determined in Ad E1-transformed cells. Surprisingly, it was found that a p53-responsive promoter is highly active in Ad E1-transformed cells and further activated only 3- to 4-fold (compared to 200-fold in p53(-/-) cells) by exogenously expressed p53 or p53mt24-28, a p53 mutant that is transcriptionally active but unable to bind the E1B 55K. On the other hand, the transient overexpression of E1B 55K led to a strong downregulation of a p53-responsive promoter relative to its baseline activity in Ad E1-transformed cells but not in p53(-/-) cells. COS-7 cells, transformed by simian virus 40 (SV40), also showed constitutive p53 activity, whereas HeLa cells, transformed with oncogenic human papillomavirus, did not. Upon stable transfection, Ad E1-transformed cells but not p53(-/-) cells gave rise to colonies that expressed exogenous p53 or p53mt24-28 but, nonetheless, grew at near-wild-type rates. It is proposed that E1B 55K or the SV40 tumour antigen are saturated by the p53 protein, which accumulates in virus-transformed cells, leaving a proportion of active p53 molecules. The transformation of cells by the Ad E1 genes confers permissiveness for active p53, conceivably by inactivating the relevant products of p53 target genes that would otherwise prevent cell growth. Thus, Ad-transformed cells contain and tolerate active p53.
J Gen Virol 2002 Aug
PMID:Adenovirus E1-transformed cells grow despite the continuous presence of transcriptionally active p53. 1212 69

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8-encoded viral interferon regulatory factor (vIRF) transforms NIH3T3 cells, represses interferon signal transduction and regulates the expression of other KSHV genes. Here, we have shown that vIRF is a transcriptional activator and auto-activates its own expression. Ectopic expression of vIRF activated the vIRF promoter in KSHV-negative 293, COS7, HeLa and BJAB cell lines in a dose-dependent fashion in a reporter assay and the expression of vIRF transcripts from endogenous viral genomes in BCBL-1 and BC-1 cells latently infected with KSHV. Deletion analysis identified two cis elements, named Vac1 and Vac2, in the vIRF promoter that were responsive to vIRF activation. vIRF auto-activation via Vac1 but not Vac2 was repressed by Tis, a transcriptional silencer in the vIRF promoter. Neither Vac1 nor Vac2 contain any interferon-stimulated response element (ISRE)-like sequences and are unresponsive to induction with interferon-beta and -gamma. These results indicate that KSHV uses the mechanism of auto-activation to regulate the expression of a viral transforming protein to efficiently evade host tumour suppressor pathways.
J Gen Virol 2003 Feb
PMID:Auto-activation of the transforming viral interferon regulatory factor encoded by Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8). 1256 May 64

Human T-cell leukaemia virus type 1 (HTLV-I), the aetiological agent of adult T-cell leukaemia (ATL) and tropical spastic paraparesis (TSP/HAM), transforms human T-cells in vivo and in vitro. The Tax protein of HTLV-I is essential for cellular transformation as well as viral and cellular gene transactivation. The interaction of Tax with cellular proteins is critical for these functions. We previously isolated and characterized a novel Tax-binding protein, TRX (TAX1BP2), by screening a Jurkat T-cell cDNA library. In the present study, we present evidence that the tumour suppressor p53 targets the TRX protein for proteasome degradation. Pulse-chase experiments revealed that p53 enhanced the degradation of TRX protein and reduced the half-life from 2.0 to 0.25 h. p53 mutants R248W and R273H enhance TRX degradation suggesting a transcriptionally independent mechanism. Both HTLV-I Tax and the proteasome-specific inhibitor MG132 inhibited p53-mediated TRX protein degradation. These results suggest that TRX degradation is mediated through activation of the proteasome protein degradation pathway independent of transcriptional function of p53. Our results provide the first experimental evidence that Tax inhibits transcription-dependent and independent functions of p53.
J Gen Virol 2003 Apr
PMID:P53 facilitates degradation of human T-cell leukaemia virus type I Tax-binding protein through a proteasome-dependent pathway. 1265 90

Epstein-Barr virus (EBV) has the ability to promote cell cycle progression following the initial infection of primary resting B-lymphocytes and to cause cell cycle arrest at the onset of the viral replicative cycle. Various mechanisms have been proposed for the proliferative effects, including the up-regulation of cyclin D2 by the viral EBNA-2 and EBNA-LP proteins, direct binding of EBNA3C to the retinoblastoma protein (pRb), and down-regulation of the p16(INK4A) tumour suppressor by the viral LMP1 product. To try to gain insight into the relative importance of these mechanisms, the ability of EBV to immortalize lymphocytes from an individual who is genetically deficient for p16(INK4A) was examined. From detailed analyses of the resultant lymphoblastoid cell lines it is concluded that p16(INK4A) status has little bearing on EBV's ability to manipulate the cell cycle machinery and a model to accommodate the previously proposed routes taken by EBV to bypass the restriction point is presented.
J Gen Virol 2004 Jun
PMID:p16(INK4A)-independence of Epstein-Barr virus-induced cell proliferation and virus latency. 1516 19

Human papillomaviruses (HPVs) are aetiological agents for genital warts and cervical cancer, the different pathologies of which are dependent on the type of HPV infection. Oncogenic HPV types associated with cancer are carcinogens by virtue of their oncogene products, which target key regulators of cell proliferation and apoptosis. The viral E6 protein from oncogenic HPV types plays a central role in carcinogenesis by exploiting the cellular proteasome degradation pathway in order to mediate the degradation of cellular proteins, most notably the prototype tumour suppressor protein p53. Much less is known about the cellular targets of E6 from the non-oncogenic HPV types associated with genital warts. It is also unclear what factors influence the level and stability of the viral E6 proteins in cells. This report demonstrates that both oncogenic and non-oncogenic HPV E6 proteins (from types 18 and 11, respectively) are ubiquitinated and targeted for degradation by the 26S proteasome. E6 domains required for the induction of p53 or DLG degradation, or E6AP binding, are not involved in proteasome-mediated degradation of HPV-18 E6. These results provide insight into the cellular modulation of E6 protein levels from both high-risk and low-risk HPV types.
J Gen Virol 2004 Jun
PMID:Ubiquitination and proteasome degradation of the E6 proteins of human papillomavirus types 11 and 18. 1516 24

An important characteristic of the E6 proteins derived from cancer-associated human papillomaviruses (HPVs) is their ability to target cellular proteins for ubiquitin-mediated degradation. Degradation of the p53 tumour suppressor protein by E6 is known to involve the cellular ubiquitin ligase, E6-AP; however, it is presently not known how E6 targets the Drosophila discs large (Dlg) tumour suppressor and the membrane-associated guanylate kinase inverted (MAGI) family of proteins for degradation. By using an in vitro E6-AP immunodepletion assay, these targets were tested for degradation in a E6-AP-dependent manner. The data showed clearly that E6 can direct the degradation of Dlg and the MAGI family of proteins in the absence of E6-AP in this in vitro system. These results provide compelling evidence for the role of E6-associated ubiquitin ligases other than E6-AP in the degradation of certain E6 targets.
J Gen Virol 2004 Oct
PMID:Degradation of hDlg and MAGIs by human papillomavirus E6 is E6-AP-independent. 1544 42

Survivin has recently been identified as a novel member of the inhibitor of apoptosis (IAP) gene family. The product of this gene not only suppresses apoptosis but also controls cell division. Survivin is undetectable in most terminally differentiated normal tissues but is expressed in embryonic and fetal organs and is present in most malignant tumours. Human papillomaviruses (HPV) are thought to play an important role in the development of cervical cancer. By interfering in the cell cycle, the viral oncoproteins (E6 and E7) can induce the immortalization of the host cell. The transcriptional effects of the HPV-16 E6 and E7 proteins on the survivin promoter in transiently transfected cell lines using luciferase tests were examined. HPV-16 E6, but not E7, was found to significantly transactivate the survivin promoter. Experiments performed in different cancer cell lines and with different E6 mutants indicated that the effect of E6 on the survivin promoter is largely dependent on p53 status. In accordance with this, the p53 tumour suppressor protein downregulated the expression of survivin. As E6 is able to interact with p53 and induces its ubiquitin-dependent degradation, it appears that the transactivation effect of E6 on survivin is mediated by the p53 degradation pathway. Transduction of HPV-16 E6 and E7 into human embryonic fibroblast cells showed that the HPV oncoproteins can upregulate endogenous survivin mRNA. Importantly, cell cycle synchronization experiments showed that the effect of HPV-16 E6 on survivin transcription is independent of the cell cycle.
J Gen Virol 2006 Feb
PMID:Effects of human papillomavirus type 16 oncoproteins on survivin gene expression. 1643 13

The N-terminal 198 residues of NS3 (NS3-N) of Hepatitis C virus (HCV) subtype 1b obtained from 29 patients, as well as full-length NS3 (NS3-Full), were analysed for their subcellular localization, interaction with the tumour suppressor p53 and serine protease activity in the presence and absence of the viral cofactor NS4A. Based on the subcellular-localization patterns in the absence of NS4A, NS3-N sequences were classified into three groups, with each group exhibiting either dot-like, diffuse or a mixed type of localization. Chimeric NS3-Full sequences, each consisting of an individual NS3-N and a shared C-terminal sequence, showed the same localization patterns as those of the respective NS3-N. Site-directed mutagenesis experiments revealed that a single or a few amino acid substitutions at a particular position(s) of NS3-N altered the localization pattern. Interestingly, NS3 of the dot-like type, either NS3-N or NS3-Full, interacted with p53 more strongly than that of the diffuse type, in both the presence and the absence of NS4A. Moreover, NS3-N of the dot-like type suppressed trans-activating activity of p53 more strongly than that of the diffuse type. Serine protease activity did not differ significantly between the two types of NS3. In HCV RNA replicon-harbouring cells, physical interaction between NS3 and p53 was observed consistently and p53-mediated transcriptional activation was suppressed significantly compared with HCV RNA-negative control cells. Our results collectively suggest the possibility that NS3 plays an important role in the hepatocarcinogenesis of HCV by interacting differentially with p53 in an NS3 sequence-dependent manner.
J Gen Virol 2006 Jun
PMID:NS3 protein of Hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner. 1669 Sep 37


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