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

The retinoblastoma susceptibility gene is a tumour suppressor and its product retinoblastoma protein (pRb) has been known for 10 years as a repressor of progression towards S phase. Its major activity was supposed to be sequestration or inactivation of the transcription factor E2F which is required for activation of S phase genes. However, within recent years growing evidence has been accumulating for a more general function of pRb at both the transcriptional level and the cellular level. pRb not only regulates the activity of certain protein-encoding genes but also the activity of RNA polymerase pol I and pol III transcription. This protein appears to be the major player in a regulatory circuit in the late G1 phase, the so-called restriction point. Moreover, it is involved in regulating an elusive switch point between cell cycle, differentiation and apoptosis. Here, it seems to cooperate with another major tumour suppressor, p53. Thus, pRb sits at the interface of the most important cell-regulatory processes and therefore deserves close attention by specialists from different fields of research. This review provides an introduction to the complex functions of pRb.
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PMID:The retinoblastoma protein: a master regulator of cell cycle, differentiation and apoptosis. 921 14

Hepatitis B virus X protein (HBX) was studied for its capacity to form a specific complex with the retinoblastoma tumour suppressor protein (pRB), and for its effect on the expression of pRB. HBX was synthesized by in vitro transcription and translation in the presence of [35S]methionine. The synthesized HBX was assayed for its binding to a glutathione-S-transferase (GST)-pRB fusion protein bound to Sepharose beads. The in vivo binding was investigated by a co-immunoprecipitation and Western blot analysis of the cell extract from a CMV-HBX-transfected hepatoblastoma cell line, Hep G2 cells. These experiments demonstrated that HBX was unable to form a detectable complex with pRB. However, the level of pRB increased considerably in Hep G2 cells transfected with CMV-HBX clone. The alteration of pRB expression by HBX could be a mechanism, contributing to the development of hepatocellular carcinoma (HCC) in human.
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PMID:Effect of hepatitis B virus X protein on the expression of retinoblastoma gene product. 938 99

Ras proteins act as molecular switches, responding to signals by entering the active GTP-bound, rather than the inactive GDP-bound, state. The inhibition of normal Ras proteins by microinjection of neutralizing antibody or expression of dominant-negative mutants has shown that Ras signalling is required for growth factors to stimulate DNA synthesis [1] [2], but the link between Ras and the cell-cycle machinery is not clear. Regulation of the phosphorylation state of the retinoblastoma protein (pRb), the product of the tumour suppressor gene Rb, is a key event in the progression of cells from G1 phase into S phase. In growth-arrested or early G1 cells, pRb is hypophosphorylated and binds to transcription factors of the E2F family [3]. These pRb-E2F complexes act to suppress gene transcription required for entry into DNA synthesis either by preventing E2F from stimulating transcription or by actively repressing transcription [4]. During G1, cyclin-dependent kinases (CDKs) become activated and phosphorylate pRb at multiple sites, leading to the dissolution of pRb-E2F complexes and gene transcription [5]. Here, we have tested the hypothesis that Ras signalling is required for the inactivation of pRb. A neutralizing antibody directed against p21Ras was microinjected into cells derived from mutant mouse embryos that lack Rb or CDK inhibitors (CDKIs). Cells without pRb or the p16 CDKI were more resistant to the inhibitory effects of the anti-Ras antibody. DNA synthesis in some tumour cell lines was completely resistant to the anti-Ras injection, indicating that p21Ras is required for pRb inactivation but also has other functions in cell-cycle progression.
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PMID:Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein. 939 36

Regulation of both the cell cycle and gene transcription is essential for orderly progression of cell growth and division. Recent results on the structures of two cyclins, cyclin A and cyclin H, and two transcription factor mediator proteins, TFIIB and the A pocket region of the retinoblastoma tumour suppressor protein (Rb), show that they share domains with a strikingly similar alpha-helical topology, despite remote sequence identity.
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PMID:The cyclin box fold: protein recognition in cell-cycle and transcription control. 943 29

The pocket domain of the retinoblastoma (Rb) tumour suppressor is central to Rb function, and is frequently inactivated by the binding of the human papilloma virus E7 oncoprotein in cervical cancer. The crystal structure of the Rb pocket bound to a nine-residue E7 peptide containing the LxCxE motif, shared by other Rb-binding viral and cellular proteins, shows that the LxCxE peptide binds a highly conserved groove on the B-box portion of the pocket; the A-box portion appears to be required for the stable folding of the B box. Also highly conserved is the extensive A-B interface, suggesting that it may be an additional protein-binding site. The A and B boxes each contain the cyclin-fold structural motif, with the LxCxE-binding site on the B-box cyclin fold being similar to a Cdk2-binding site of cyclin A and to a TBP-binding site of TFIIB.
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PMID:Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. 949 40

The rate of protein synthesis is a critical determinant of cellular growth. Abnormal activation of this process is a frequent feature of transformed and tumour cells. Several distinct components of the translation apparatus have been shown to be deregulated in response to malignant transformation. Indeed, overexpression of certain translation factors has been found to predispose cells to transformation or even initiate it. The latest twist to this story comes from the discovery that the retinoblastoma protein RB plays a major role in restricting the production of tRNA and rRNA. RB is an important tumour suppressor. Its ability to limit the synthesis of these principle determinants of biosynthetic capacity could provide a mechanism for restraining cell growth. The loss of this control may constitute a significant step towards tumour progression.
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PMID:Transcription by RNA polymerases I and III: a potential link between cell growth, protein synthesis and the retinoblastoma protein. 950 Jun 74

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.
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PMID:Molecular genetic analysis of familial neuroblastoma. 951 25

Two opposing enzymatic reactions control the activity of the retinoblastoma tumour suppressor protein, pRB. Phosphorylation inactivates pRB's ability to sequester miscellaneous cellular proteins, mostly involved in regulating gene transcription, whereas pRB dephosphorylation restores this ability. For some time now it has been suspected that members of the cyclin/cyclin-dependent kinase (cyclin/cdk) family mediate pRB inactivation. Recent results indicate that pRB phosphorylation is not executed by single kinase but by a combination of cyclin/cdks, each one phosphorylating a subset of pRB's phosphorylation sites. The different kinases appear to be activated by growth factors through distinct signal transduction pathways. This lends itself to an attractive model whereby pRB phosphorylation may constitute an integration point for these signalling pathways, perhaps allowing cell cycle progression only when concurrent activation of these signalling pathways has been achieved.
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PMID:Control of pRB phosphorylation. 952 1

The most frequent structural chromosome abnormality in chronic lymphocytic leukaemia (CLL) is deletion at chromosome 13q14. Studies with Southern blot hybridisation have revealed deletions in the region located telomeric of the retinoblastoma gene in more than 40% of cases. The highest frequency of homozygous deletions has been found at the D13S319 locus and it is likely that a new tumour suppressor gene is located close to this region. We have analysed deletions in the D13S319 region in 20 selected CLL patients using conventional cytogenetic analysis, fluorescence in situ hybridisation (FISH) and Southern blot hybridisation. FISH and Southern hybridisation are equally efficient in detecting deleted clones in our study. However, FISH analysis indicate that subclones with different numbers of alleles in the D13S319 region can exist simultaneously. The cytogenetic analyses confirm that clones with different chromosomal abnormalities can occur in patients with CLL and that 13q14 deletions can be limited to one of these subclones. Furthermore, the FISH analyses show that trisomy 12 and deletion of 13q14 can occur in the same cell clone. Finally, our study confirms that mitogen stimulation of peripheral blood cells from CLL patients before FISH analysis may result in a sharp increase in normal appearing cells, which can hide leukaemic clones with deletions in the D13S319 region.
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PMID:A FISH cosmid 'cocktail' for detection of 13q deletions in chronic lymphocytic leukaemia--comparison with cytogenetics and Southern hybridization. 959 68

Loss of genetic material on chromosomes 13q and 17 has been suggested to be of importance in the initiation and progression of female breast cancer, but their involvement is less well illustrated in male breast carcinomas. The present study was designed to investigate the incidence of allelic loss and microsatellite instability for chromosomes 13q, 17p and 17q in 13 sporadic male breast carcinomas using matched normal-tumour DNA samples and seven polymorphic microsatellite markers. Genetic imbalance was found in one or more informative markers in 85% of the patients, with more frequent loss of heterozygosity and microsatellite instability at loci on chromosome 13q. Thus, a high incidence of allelic losses was observed at the retinoblastoma gene (4/6) and likewise at the D13S263 locus (7/12), which also exhibited the highest frequency of microsatellite instability. The intragenic microsatellite in intron 1 of the TP53 gene on chromosome 17p revealed loss of heterozygosity in 3 of 8 informative patients. The investigated proximal region of chromosome 13q is postulated to harbour several potential tumour suppressor genes associated with female breast cancer. The high incidence of allelic losses at the D13S263 microsatellite, located distal to both the BRCA2 and the Brush-1 loci but proximal to the retinoblastoma gene, possibly indicates the presence of an additional tumour suppressor gene which may be involved in male breast carcinomas. However, this hypothesis needs verification in an extended study of male breast carcinomas.
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PMID:Frequent allelic losses on chromosome 13q in human male breast carcinomas. 961 88


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