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)

Physical associations between cyclins, viral oncogenes and tumour suppressor genes imply a central role for cyclins in growth control. Cyclin D1 was identified as a candidate oncogene (PRAD1) in tumour-specific DNA rearrangements and is suspected to be a contributor to several types of neoplasms including breast cancer. Cyclin D1 also rescues G1 cyclin-defective Saccharomyces cerevisiae, and is a growth-regulated gene. Despite evidence suggesting that cyclin D1 is an oncogene, its ability to transform cells directly in culture remains controversial. To evaluate its potential to deregulate growth in vivo in a physiologically relevant tissue we overexpressed cyclin D1 in mammary cells in transgenic mice. We report here that overexpression of cyclin D1 resulted in abnormal mammary cell proliferation including the development of mammary adenocarcinomas. We conclude that overexpression of cyclin D1 deregulates cell proliferation and can induce tumorigenic changes in mammary tissues, suggesting that cyclin D1 indeed plays an important oncogenic role in breast cancer.
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PMID:Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. 820 95

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

Several genes have been identified as targets for transcriptional activation by the p53 tumour suppressor protein. Rodent cyclin G was previously identified as a p53 responsive gene and in order to assess the role played by cyclin G as a mediator of p53 function in humans cells we have isolated full length human cyclin G1 and identified a related gene designated cyclin G2. Both human G-cyclins are induced by the DNA damaging agent actinomycin-D and although the induction of cyclin G1 is clearly p53 dependent, activation of cyclin G2 expression was observed in the absence of p53. Based on sequence similarity, the G-cyclins and the recently identified cyclin I form a distinct sub-group within the larger cyclin family, possibly reflecting some degree of functional similarity.
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PMID:Characterisation of human cyclin G1 and G2: DNA damage inducible genes. 880 1

Mutations in the p53 tumour suppressor gene are the most common genetic alteration found in human cancers. Most of them are accompanied by stabilization of the protein, which renders it detectable through immunohistochemical techniques. Although p53 expression is a very common finding in Hodgkin's disease (HD), the status of the p53 gene is scarcely known, due to the difficulty in sequencing this gene in a lesion in which tumour cells are thought to constitute a very minor subpopulation, diluted in a background of supposedly benign cells. The pattern of expression of two downstream p53 proteins (MDM2 and p21 WAF1/CIP1, was studied as an indirect way of assessing p53 gene status. MDM2 is a wild-p53 inducible protein which may form a complex with p53, abrogating its function, as has been found in human sarcomas and other malignancies. p21WAF1/CIP1 is another protein inducible by wild-type p53, involved in inhibiting cell-cycle progression, through binding to cyclin/cyclin-dependent-kinase complexes. MDM2 and p21WAF1/CIP1 immunostaining was detected in all the cases analysed, independently of histological type, and were mainly present in Sternberg-Reed and Hodgkin (H & SR) cells. These immunohistochemical results were confirmed by Western blotting. To study the cause of MDM2 protein accumulation, MDM2 mRNA expression was also investigated by reverse transcription polymerase chain reaction (RT-PCR). The results show the presence of MDM2 transcripts in all cases of HD, albeit at lower levels than those found in reactive lymphoid tissue. These results seem to support the hypothesis that p53 is transcriptionally active in at least some of the H & SR cells in HD, and is able to induce MDM2 and p21WAF1/CIP1 protein expression.
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PMID:MDM2 and p21WAF1/CIP1, wild-type p53-induced proteins, are regularly expressed by Sternberg-Reed cells in Hodgkin's disease. 894 16

Continuous antiprogestin administration to hormone replaced, castrate monkeys inhibits estrogen-induced endometrial proliferation through mechanisms which remains unclear. To elucidate the molecular mechanisms of RU486-induced endometrial suppression, we treated six intact female cynomolgus monkeys on cycle days 2-22 sequentially with placebo, RU486 (1 mg/kg/day) and levonorgestrel (LNG) (2 microg/kg/day) intramuscularly (i.m.), with uterine wedge sections and endometrial biopsies collected on day 22 of each cycle. The uterine sections were evaluated for morphology, mitosis and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Changes in the mRNA levels of ER, PR, cyclin-B and tumour suppressor gene p21 were assessed using co-amplification with beta-actin by reverse transcriptase-polymerase chain reaction (RT-PCR). Administration of RU486 uniformly resulted in characteristic suppression of endometrium with few mitosis, dense stroma and simple glands, whereas the effects of LNG were less uniform. Following RU486 administration, the levels of endometrial ER and PR mRNA were comparable to proliferative phase endometrium, and significantly higher than those seen in the secretory endometrium, indicating that some of the biological actions of E2 were not inhibited during RU486 treatment. Despite scarce mitosis, PCNA was readily detectable in all samples. Curiously, in comparison to secretory phase controls, the levels of cyclin-B, but not p21, mRNA were markedly increased following RU486. The effects of LNG on the levels of these mRNA species varied, with mean levels falling between those of the secretory phase controls, and RU486-treated specimens. The increase in cyclin-B mRNA and lack of mitosis suggests that anti-proliferative actions of RU486 in the primate endometrium might be associated with a cell-cycle block at the G2-M interphase. Whether mechanisms similar to these are associated with the beneficial clinical effects of RU486 seen in the treatment of various hormone dependent maladies remains to be determined.
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PMID:Endometrial effects of RU486 in primates--antiproliferative action despite signs of estrogen action and increased cyclin-B expression. 901 Mar 33

Mouse p57(Kip2) arrests cells in G1 by functioning as a strong inhibitor of several G1 cyclin/Cdk complexes (Lee et al., 1995; Matsuoka et al., 1995; Sherr and Roberts, 1995). Human p57(KIP2) has been suggested to be a tumour suppressor gene because of its location at 11p15.5 which frequently undergoes maternal allele LOH in several types of cancer (Matsuoka et al., 1995; Sherr and Roberts, 1995; Hatada and Mukai, 1995). This suggestion was supported by the discovery that mouse p57(Kip2) is imprinted with expression from only the maternally inherited allele (Hatada and Mukai, 1995). Interestingly, p57(KIP2) is several hundred kilobases from the imprinted H19 and IGF2 genes which are involved in growth regulation (Hoovers et al., 1995). Here we show that human p57(KIP2) is imprinted with expression from the maternal allele. However, unlike the mouse, the imprinting is incomplete with significant expression from the paternal allele depending on the tissue examined. We have also shown that the imprinting of p57(KIP2) occurs independently of the H19/IGF2 domain and thus there must be at least two imprinted domains in 11p15.5. Finally, by examining Wilms tumours we have shown that following maternal 11p LOH, p57(KIP2) was expressed from the paternal allele. Therefore, p57(KIP2) cannot function as an imprinted tumour suppressor gene, at least in Wilms tumour.
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PMID:Human p57(KIP2) defines a new imprinted domain on chromosome 11p but is not a tumour suppressor gene in Wilms tumour. 912 69

The pocket region of retinoblastoma tumour suppressor (Rb) is essential for tumour suppressing activity. The Rb pocket is primarily composed of two domains, A and B. We have determined the X-ray crystal structure of domain A (residues 378-562) at 2.3 A resolution. Domain A consists of nine alpha-helices. The overall arrangement of helices in domain A is remarkably similar to the cyclin-box folds found in the crystal structures of cyclin A and TFIIB. This structure, along with domain B which is predicted to be homologous to the cyclin-box, suggests that the Rb pocket is composed of two cyclin-box fold domains. We present the structural/functional features of the Rb pocket, and the potential binding region for cellular or viral proteins within domain A.
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PMID:Structural similarity between the pocket region of retinoblastoma tumour suppressor and the cyclin-box. 914 10

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

Many tumour therapies act by inducing a cellular damage response pathway mediated by the tumour suppressor protein p53. Alternative outcomes of p53 induction include apoptosis or transient cell-cycle arrest, both thought to require the transcriptional activity of wild-type p53. Current research highlights the action of a p53-activated gene, p21Cip1/WAF1/Sdi1, which encodes a cyclin-kinase inhibitor important in mediating p53-dependent cell-cycle arrest, while programmed cell death in response to DNA damage requires transcriptionally active p53 but not activation of p21Cip1/WAF1/Sdi1. This review examines the roles of p53 and p21Cip1/WAF1/Sdi1 in controlling cell proliferation, in the light of a new study on expression of p53 and p21Cip1/WAF1/Sdi1 in squamous cell carcinoma of the larynx.
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PMID:Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21Cip1/WAF1/Sdi1. 939 24

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


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