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)

Simian virus 40 (SV40) has been linked to human cancer, as has osteosarcoma (OS). Although significant discrepancies exist in the frequency, evidence that the virus plays a causative role in some malignancies is mounting. The large-T-antigen and significant SV40 oncoprotein, bind and inactivate the tumour suppressor genes p53 and pRb, which play a key role in osteosarcoma development. We analysed 277 OS samples from two different European countries (154 OS samples from Hungary and 123 from Germany). To ascertain the prevalence of SV40 in the general population, additional blood samples from healthy volunteers from the two countries (166 Hungarian and 149 German) were analysed. To reach an appropriate detection level, we investigated a real-time quantitative PCR-based assay for the detection and quantification of SV40 <10 copies in 500 ng of genomic DNA. We detected SV40 in 52% (143/277) of the OS samples analysed. In detail, we saw differences in the distribution of SV40 between the two countries. Of the Hungarian OS samples, 74% (114/154) showed high amounts of SV40 (>100 copies), whereas only 22% (29/123) of the German OS samples harbour small amounts of SV40 ( approximately 10 copies). SV40 was detected in 8 of 60 German tumour samples (14%) and 21 of 63 German blood samples (33%) from OS patients. In the peripheral blood of healthy volunteers we found only weak SV40 positivity (<10 copies) in the two countries with a somewhat higher frequency in Hungarian 30/166 (18%) than in German blood samples 2/149 (1.3%). No sequence variations were found in SV40-positive samples from the two countries. Our data demonstrate significant differences in the prevalence and quantity of SV40 in OS of these different European geographical origins with a lower frequency in the blood samples of healthy volunteers from the two countries, underlining again the geographical differences previously described by other investigators.
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PMID:Evaluation of SV40 in osteosarcoma and healthy population: a Hungarian-German study. 1914 98

The pRb tumour suppressor protein has a central role in coordinating early cell cycle progression. An important level of control imposed on pRb occurs through post-translational modification, for example, phosphorylation. We describe here a new level of regulation on pRb, mediated through the targeted methylation of lysine residues, by the methyltransferase Set7/9. Set7/9 methylates the C-terminal region of pRb, both in vitro and in cells, and methylated pRb interacts with heterochromatin protein HP1. pRb methylation is required for pRb-dependent cell cycle arrest and transcriptional repression, as well as pRb-dependent differentiation. Our results indicate that methylation can influence the properties of pRb, and raise the interesting possibility that methylation modulates pRb tumour suppressor activity.
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PMID:Lysine methylation regulates the pRb tumour suppressor protein. 2014 18

Oncogene-induced senescence acts as a barrier against tumour formation and has been implicated as the mechanism preventing the transformation of benign melanocytic lesions that frequently harbour oncogenic B-RAF or N-RAS mutations. In the present study we systematically assessed the relative importance of the tumour suppressor proteins p53, p21(Waf1), pRb and p16(INK4a) in mediating oncogene-induced senescence in human melanocytes. We now show that oncogenic N-RAS induced senescence in melanocytes is associated with DNA damage, a potent DNA damage response and the activation of both the p16(INK4a)/pRb and p53/p21(Waf1) tumour suppressor pathways. Surprisingly neither the pharmacological inhibition of the DNA damage response pathway nor silencing of p53 expression had any detectable impact on oncogene-induced senescence in human melanocytes. Our data indicate that the pRb pathway is the dominant effector of senescence in these cells, as its specific inactivation delays the onset of senescence and weakens oncogene-induced proliferative arrest. Furthermore, we show that although both p16(INK4a) and p21(Waf1) are upregulated in response to N-RAS(Q61K), the activities of these CDK inhibitors are clearly distinct and only the loss of p16(INK4a) weakens senescence. We propose that the ability of p16(INK4a) to inhibit the cyclin D-dependent kinases and DNA replication, functions not shared by p21(Waf1), contribute to its role in senescence. Thus, in melanocytes with oncogenic signalling only p16(INK4a) can fully engage the pRb pathway to alter chromatin structure and silence the genes that are required for proliferation.
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PMID:The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence. 2015 37

Mutation of the retinoblastoma gene (RB1) tumour suppressor occurs in one-third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma. Numerous functions have been ascribed to the product of the human RB1 gene, the retinoblastoma protein (pRb). The best known is pRb's ability to promote cell-cycle exit through inhibition of the E2F transcription factors and the transcriptional repression of genes encoding cell-cycle regulators. In addition, pRb has been shown in vitro to regulate several transcription factors that are master differentiation inducers. Depending on the differentiation factor and cellular context, pRb can either suppress or promote their transcriptional activity. For example, pRb binds to Runx2 and potentiates its ability to promote osteogenic differentiation in vitro. In contrast, pRb acts with E2F to suppress peroxisome proliferator-activated receptor gamma subunit (PPAR-gamma), the master activator of adipogenesis. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that pRb might play a role in the choice between these two fates. However, so far, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis. Our data show that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.
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PMID:Rb regulates fate choice and lineage commitment in vivo. 2083 58

As a critical target for cyclin-dependent kinases (Cdks), the retinoblastoma tumour suppressor protein (pRb) controls early cell cycle progression. We report here a new type of regulation that influences Cdk recognition and phosphorylation of substrate proteins, mediated through the targeted methylation of a critical lysine residue in the Cdk substrate recognition site. In pRb, lysine (K) 810 represents the essential and conserved basic residue (SPXK) required for cyclin/Cdk recognition and phosphorylation. Methylation of K810 by the methyltransferase Set7/9 impedes binding of Cdk and thereby prevents subsequent phosphorylation of the associated serine (S) residue, retaining pRb in the hypophosphorylated growth-suppressing state. Methylation of K810 is under DNA damage control, and methylated K810 impacts on phosphorylation at sites throughout the pRb protein. Set7/9 is required for efficient cell cycle arrest, and significantly, a mutant derivative of pRb that cannot be methylated at K810 exhibits compromised cell cycle arrest. Thus, the regulation of phosphorylation by Cdks reflects the combined interplay with methylation events, and more generally the targeted methylation of a lysine residue within a Cdk-consensus site in pRb represents an important point of control in cell cycle progression.
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PMID:Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein. 2111 16

To investigate polyomavirus infection in wild rodents, we analysed DNA samples from the spleens of 100 wild rodents from Zambia using a broad-spectrum PCR-based assay. A previously unknown polyomavirus genome was identified in a sample from a multimammate mouse (Mastomys species) and the entire viral genome of 4899 bp was subsequently sequenced. This viral genome contained potential ORFs for the capsid proteins, VP1, VP2 and VP3, and early proteins, small t antigen and large T antigen. Phylogenetic analysis showed that it was a novel member of the family Polyomaviridae, and thus the virus was tentatively named mastomys polyomavirus. After transfection of the viral genome into several mammalian cell lines, transient expression of the VP1 and large T antigen proteins was confirmed by immunoblotting and immunocytochemical analyses. Comparison of large T antigen function in mastomys polyomavirus with that in rhesus monkey polyomavirus SV40 and human polyomavirus JC virus revealed that the large T antigen from mastomys polyomavirus interacted with the tumour suppressor protein pRb, but not with p53.
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PMID:Detection and characterization of a novel polyomavirus in wild rodents. 2117 25

We have analysed the role of RBR (retinoblastoma related), the Arabidopsis homologue of the tumour suppressor Retinoblastoma protein (pRb), during meiosis. We characterise the rbr-2 mutation, which causes a loss of RBR in male meiocytes. The rbr-2 plants exhibit strongly reduced fertility, while vegetative growth is generally unaffected. The reduced fertility is due to a meiotic defect that results in reduced chiasma formation and subsequent errors in chromosome disjunction. Immunolocalisation studies in wild-type meiocytes reveal that RBR is recruited as foci to the chromosomes during early prophase I in a DNA double-strand-break-dependent manner. In the absence of RBR, expression of several meiotic genes is reduced. The localisation of the recombinases AtRAD51 and AtDMC1 is normal. However, localisation of the MutS homologue AtMSH4 is compromised. Additionally, polymerisation of the synaptonemal complex protein AtZYP1 is abnormal. Together, these data indicate that loss of RBR during meiosis results in a reduction of crossover formation and an associated failure in chromosome synapsis. Our results indicate that RBR has an important role in meiosis affecting different aspects of this complex process.
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PMID:Retinoblastoma protein is essential for early meiotic events in Arabidopsis. 2132 73

The process of how a benign tumour turns invasive and capable to survive in distant organs remains poorly understood, despite the evidence that metastasis formation is the primary cause of cancer patient mortality. This ignorance is partly due to the lack of appropriate animal models from which to investigate this complex process. The retinoblastoma (Rb) tumour suppressor pathway (pRb/E2F) is mutated in almost all human tumours, and a number of laboratories have now established pRb- or E2F-deficient mouse models. Consistent with the role of mutation in retinoblastoma in cancer biology, Rb heterozygous mice are prone to develop tumours. Among the ensuing tumours, the medullary thyroid carcinomas (MTCs) have a lessened tendency to form secondary cancers and metastases. Intriguingly, if an E2f3 mutation is introduced in this genetic background, more aggressive MTCs develop, which metastasize more frequently. Gene chip microarrays, however, provide an unbiased approach for examining the genome-wide expression levels and enable identification of a large set of metastasis-enriched gene sets. The identified genes may simply represent putative markers of the disease stage. Alternatively, genes may be identified that causally determine a link to the onset of metastasis. We describe the use of gene chip microarrays for identification of putative markers enriched in metastatic mouse MTCs. The chapter details how the most promising candidates are verified using additional methods, such as quantitative real-time PCR. In this case, co-transfection of the E2F-transcription factor using a heterologous reporter gene system is suggestive of E2Fs directly regulating putative metastasis markers.
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PMID:Genes involved in the metastatic cascade of medullary thyroid tumours. 2267 36

Salivary gland tumors (SGT) are a heterogeneous group of lesions. There is conflicting data concerning the molecular events involving the tumour suppressor retinoblastoma protein (pRb) pathway in these tumors. Few studies examined the alterations in components of the Rb pathway by immunohistochemical (IHC) methods in benign and malignant SGTs. Furthermore, recent evidence implicates human papillomavirus (HPV) in mucoepidermoid carcinoma (MEC) carcinogenesis. The purpose of our study is to examine p16(INK4A) and cyclin D1 expression in a variety of benign and malignant salivary gland tumors, and to investigate p16(INK4A) expression as a surrogate marker for HPV infection in MEC. Our series includes 30 malignant tumors [14 MEC, 6 acinic cell carcinomas (ACC), 5 polymorphous low grade adenocarcinomas (PLGA), 5 (AdCC)] and 14 benign tumors (4 benign cysts, 5 Warthin tumors and 5 pleomorphic adenomas (PA). All cases were tested by IHC for p16(INK4A) and cyclin D1. Testing for HPV wide spectrum (HPV-WS) was performed by in situ hybridization in all MEC cases. Staining intensity was recorded semi quantitatively (on a scale from 0 to 4+). Fisher's exact test and Pearson X2 test with a p < 0.05 were used. Cyclin D1 and p16(INK4A) are expressed similarly in malignant and benign tumors (p = 0.146 and p = 0.543, respectively). None of the MEC cases showed nuclear reactivity for HPV-WS. Statistical analysis showed positive correlation between cyclin D1 and p16(INK4A) expression. Our findings suggest that p16(INK4A) overexpression is likely secondary to cyclin D1 gene upregulation or amplification. Further molecular studies are warranted.
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PMID:Differential expression of p16(INK4A) and cyclin D1 in benign and malignant salivary gland tumors: a study of 44 Cases. 2331 17

Heritable retinoblastoma is associated with a germline mutation in the tumour suppressor gene RBI. The Rb protein (pRb) arises from the RB1 gene, which was the first demonstrated cancer susceptibility gene in humans. Second primary malignancies are recognised complications of retinoblastoma. Furthermore, pRb is implicated in valve remodelling in calcific aortic valve disease. We report a family with hereditary retinoblastoma and associated secondary primary malignancies. There are two interesting aspects to this family. The first is the concept of 'cancer susceptibility genes'; the RBI gene being the first reported in humans. A further feature of note is that two family members also have bicuspid aortic valves. We discuss a potential association between the gene defect responsible for retinoblastoma (with its associated propensity for further malignancies) and accelerated deterioration of the bicuspid aortic valve in the proband carrying this gene defect.
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PMID:Heritable retinoblastoma and accelerated aortic valve disease. 2359 91


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