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 closely related mammalian TGF-betas (TGF-beta 1, TGF-beta 2 and TGF-beta 3) are potent inhibitors of proliferation of many cell types in vitro. TGF-beta 1 has been demonstrated to be growth inhibitory in vivo for epithelial, endothelial, myeloid and lymphoid cells. Utilizing skin keratinocytes as a model system for studying the mechanism of TGF-beta 1-induced growth inhibition, it has been demonstrated that TGF-beta 1 rapidly inhibits transcription of the c-myc gene. Antisense c-myc oligonucleotides inhibit proliferation of keratinocytes as effectively as does TGF-beta 1, indicating that TGF-beta 1 suppression of c-myc expression is an important component of this growth inhibition. Studies utilizing DNA tumour virus transforming gene constructs have shown that the retinoblastoma gene product, pRb, or a related protein, is needed for TGF-beta 1 suppression of c-myc transcription. Thus, TGF-beta 1 may act through a tumour suppressor gene product, pRb, to suppress transcription of a proto-oncogene, c-myc, and subsequently inhibit cell proliferation.
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PMID:Regulation of epithelial proliferation by TGF-beta. 207 Jun 84

The product of the retinoblastoma susceptibility tumour suppressor gene, pRb, is a negative regulator of cell proliferation. In order to investigate the interaction between pRb and the cell cycle machinery in more detail, a functional Rb gene was reintroduced into the Rb-deficient human mammary carcinoma cell line Bt549. Since constitutive high level expression of Rb turned out to be difficult to maintain, the tetracycline-dependent gene expression system was used. A number of clones was generated which all showed low level expression in the noninduced state. Considerable induction rates were obtained. The low level of noninduced Rb expression was sufficient to induce the expression of cyclin D1 the level of which was not further increased by upregulation of Rb expression. Concomittantly, an increase in cell doubling time was observed due to retardation of the cell cycle in the G1-phase. The data suggest that limiting amounts of cyclin D1 determine, at least partly, the extent of growth-repressing properties of pRb. The inducible system allows for maintenance of Rb-reconstituted cells at a low level of expression and for their use in the investigation of downstream functions of pRb.
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PMID:Regulated expression of the retinoblastoma susceptibility gene in mammary carcinoma cells restores cyclin D1 expression and G1-phase control. 757 42

Epstein-Barr virus (EBV) efficiently converts resting human B cells into actively cycling, immortal, lymphoblastoid cell lines (LCLs). Here we show that LCLs expressing the full complement of latent viral genes are very sensitive to DNA-damaging agents such as cisplatin. The response includes a rapid accumulation of the tumour suppressor protein p53 and induction of the cellular genes mdm2 and WAF1/p21. Although the levels of Bcl2 protein and Bax mRNA appear unaltered by the activation of p53, within 24 h the majority of cells undergo apoptosis. Over-expression of wild-type p53 in an LCL also resulted in apoptosis; this was preceded by the dephosphorylation of the retinoblastoma gene product, pRb. Primary resting B cells showed no response to cisplatin and even after drug treatment, p53 remained undetectable. However, after infection with EBV, p53 gene expression was induced to a similar level to that found in mitogen-activated B cells. When the physiologically activated primary B cells were exposed to cisplatin, although p53 accumulated as in LCLs, the outcome was growth-arrest rather than gross cell death. We conclude that, in contrast to the transformation of fibroblasts by adenovirus, SV40 or HPV, when B cells become activated and immortalized by EBV they are sensitized to the p53-mediated damage response. When the resulting LCLs are treated with genotoxic agents such as cisplatin, they are unable to arrest like normal cells because they are driven to proliferate by EBV and consequently undergo apoptosis.
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PMID:Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. 772 16

Amplification in rodent cells usually involves bridge-breakage-fusion (BBF) cycles initiated either by end-to-end fusion of sister chromatids, or by chromosome breakage. In contrast, in human cells, resistance to the antimetabolite N-(phosphonacetyl)-L-aspartate (PALA) can be mediated by several different mechanisms that lead to overexpression of the target enzyme carbamyl-P synthetase, aspartate transcarbamylase, dihydro-orotase (CAD). Mechanisms involving BBF cycles account for only a minority of CAD amplification events in the human fibrosarcoma cell line HT 1080. Here, formation of a 2p isochromosome and overexpression of CAD by other types of amplification events (and even without amplification) are much more prevalent. Broken DNA is recognized by mammalian cells with intact damage-recognition pathways, as a signal to arrest or to die. Loss of these pathways by, for example, loss of p53 or pRb tumour suppressor function, or by increased expression of ras and myc oncogenes, causes non-permissive rat and human cells to become permissive both for amplification and for other manifestations of DNA damage. In cells that are already permissive, amplification can be stimulated by overexpressing oncogenes such as c-myc or ras, or by damaging DNA in a variety of ways. To supplement genetic analysis of amplification in mammalian cells, an amplification selection has been established in Schizosaccharomyces pombe. Selection with LiCl yields cells with amplified sod2 genes in structures related to those observed in mammalian cells. The effect on amplification in S. pombe can now be tested for any mutation in a gene involved in repair of damaged DNA or in normal cellular responses to DNA damage.
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PMID:Regulation and mechanisms of gene amplification. 774 53

It is widely believed that the cellular transcription factor DRTF1/E2F integrates cell cycle events with the transcription apparatus because during cell cycle progression in mammalian cells it interacts with molecules that are important regulators of cellular proliferation, such as the retinoblastoma tumour suppressor gene product (pRb), p107, cyclins and cyclin-dependent kinases. Thus, pRb, which negatively regulates early cell cycle progression and is frequently mutated in tumour cells, and the Rb-related protein p107, bind to and repress the transcriptional activity of DRTF1/E2F. Viral oncoproteins, such as adenovirus E1a and SV40 large T antigen, overcome such repression by sequestering pRb and p107 and in so doing are likely to activate genes regulated by DRTF1/E2F, such as cdc2, c-myc and DHFR. Two sequence-specific DNA binding proteins, E2F-1 and DP-1, which bind to the E2F site, contain a small region of similarity. The functional relationship between them has, however, been unclear. We report here that DP-1 and E2F-1 exist in a DNA binding complex in vivo and that they bind efficiently and preferentially as a heterodimer to the E2F site. Moreover, studies in yeast and Drosophila cells indicate that DP-1 and E2F-1 interact synergistically in E2F site-dependent transcriptional activation.
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PMID:Functional synergy between DP-1 and E2F-1 in the cell cycle-regulating transcription factor DRTF1/E2F. 822 41

In common with the adenovirus E1A and simian virus 40 large T oncoproteins, the E7 protein of human papillomavirus (HPV) type 16 interacts with the retinoblastoma (Rb) tumour suppressor protein (pRb). The functional importance of this interaction for HPV-16 E7 protein was investigated by analysis of the transactivating function of E7 at the adenovirus E2 promoter in a set of breast tumour cell lines. Trans-activation by HPV-16 E7 in two pRb-deficient cell lines demonstrated that pRb is not essential for E7-mediated trans-activation, but reconstitution of Rb expression indicated the existence of an Rb-mediated pathway of E7 trans-activation. This pathway results from suppression by E7 of a trans-repressing function encoded by the Rb gene. The E7 protein is shown to be capable of interacting in vivo with the Rb-related protein p107. Furthermore, analysis of a fusion construct between the amino terminus of Rb and the carboxy terminus of p107 suggests that, in common with pRb, the p107 protein trans-represses the adenovirus E2 early promoter. Therefore it is proposed that the pRb-independent pathway of E7 trans-activation is a consequence of the suppression of trans-repression by p107.
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PMID:Trans-activation of the adenovirus E2 promoter by human papillomavirus type 16 E7 is mediated by retinoblastoma-dependent and -independent pathways. 824 66

p16INK4a (MTS1) is an important negative regulator of mammalian cell proliferation, acting via inhibition of CDK4/cyclin D-dependent phosphorylation of pRb to prevent progression through the G1 phase of the cell cycle. Loss of p16 activity by either gene deletion, mutation or transcriptional inactivation has now been found in a wide range of human cancers of both epithelial and mesenchymal origin, at a frequency rivalling that of p53 mutation. As a first step towards investigating its possible role as a tumour suppressor gene in thyroid tumorigenesis, we have carried out a Southern blot analysis of the p16 gene locus in a series of cell lines derived from differentiated human thyroid cancers. Homozygous deletion of the entire p16 coding sequence was observed in two of three follicular and two of four papillary cancer cell lines, but not in normal tissue or normal cells immortalised by SV40 T antigen. Given the co-existence of p16 abnormalities in primary tumours and cell lines observed in other tumour types, this high frequency of deletion suggests that p16 is a key tumour suppressor gene in the genesis of differentiated thyroid cancer.
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PMID:High frequency deletion of the tumour suppressor gene P16INK4a (MTS1) in human thyroid cancer cell lines. 882 72

The ability of mammalian cells to respond to extrinsic mitogens is downregulated in response to proliferative aging (senescence), and it is now likely that at least a subset of such lifespan checkpoints is triggered by a biological "clock" based on erosion of chromosome telomeres. This review outlines the intrinsic inhibitory signal pathways that link this clock to cell cycle arrest, focussing on the role of tumour suppressor gene products, particularly the p53 and pRb proteins. Emphasis is placed on cell-type specific differences in the timing of lifespan checkpoints, and the "choice" of the underlying inhibitory signal pathway. It is argued that such diversity may explain many differences between cell types in the selection of tumour suppressor gene mutations, providing for example a novel explanation for the difference in molecular pathology and clinical behaviour between two important subsets of human breast cancer.
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PMID:Telomeres, p53 and cellular senescence. 911 31

Many human tumours show perturbations of a pathway that includes the D-cyclins, their associated cyclin-dependent kinases, and specific kinase inhibitors. The focal point of this pathway is the product of the retinoblastoma tumour suppressor gene, pRb, which imposes a block on G1 phase progression. Thus, the major role of the cyclin D-dependent kinases is to overcome this block by initiating the phosphorylation of pRb. Excessive activity of this pathway is likely to lead to excessive cell proliferation. Conversely, accumulation of the inhibitors is associated with the cessation of cell division.
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PMID:Regulation and function of the cyclin-dependent kinase inhibitor p16CDKN2. 920 87

We have previously shown that a 20 amino acid peptide derived from the third ankyrin-like repeat of the p16CDKN2/INK4a (p16) tumour suppressor protein (residues 84-103 of the human p16 protein) can bind to cdk4 and cdk6 and inhibit cdk4-cyclin D1 kinase activity in vitro as well as block cell cycle progression through G1. Substitution of two valine residues corresponding to amino acids 95 and 96 (V95A and V96A) of the p16 peptide reduces the binding to cdk4 and cdk6 and increases its IC0.5 for kinase inhibition approximately threefold when linked to the Antennapedia homeodomain carrier sequence. The same mutations increase the IC0.5 approximately fivefold in the p16 protein. Substitution of aspartic acid 92 by alanine instead increases the binding of the peptide to cdk4 and cdk6 and the kinase inhibitory activity. The p16 peptide blocks S-phase entry in non-synchronized human HaCaT cells by approximately 90% at a 24 microM concentration. The V95A and V96A double substitution minimizes the cell cycle inhibitory capacity of the peptide whereas the D92A substitution increases its capacity to block cell cycle progression. A deletion series of the p16 derived peptide shows that a 10 residue peptide still retains cdk4-cyclin D1 kinase and cell cycle inhibitory activity. The p16 peptide inhibited S-phase entry in five cell lines tested, varying between 47-75%, but had only a limited (11%) inhibitory effect in the pRb negative Saos-2 cells at a concentration of 24 microM. Like the full length p16 protein, the p16 peptide does not inhibit cyclin E dependent cdk2 kinase activity in vitro. These data suggest that acute inhibition of CDK-cyclin D activity by a peptide derived from the INK4 family will stop cells in late G1 in a pRb dependent fashion.
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PMID:Characterization of the cyclin-dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule. 948 4


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