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)

Evolutionary aspects of human cancer can be dealt with at two levels--on the one hand long-term evolution involving hereditary effects between generations; and on the other hand evolutionary processes operating within the organisms between tissues, cells and cell constituents, which also comprise genetic alterations, selection and adaptation. These two levels of evolution can be designated as phylogenetic and ontogenetic evolution, respectively. Concerning phylogenetic evolution there must have been a strong selection against neoplastic diseases occurring at reproductive age and a variety of protective mechanisms against carcinogenic agents have been developed. Cancer is therefore primarily a disease of old age, which does not constitute a significant risk in natural populations for the simple reason that the life length is too short. The development of an individual comprises selection forces between cells and tissues, which are particularly striking for the multistage development of tumours. The accumulation of several genetic alterations in the same cells, as illustrated by the analysis of colorectal tumours, must require a pronounced clonal expansion between each event. Such selective growth effect has recently been demonstrated for the tumour suppressor gene p53 in brain tumours. Cancer often implies a break down of between balanced systems antagonistic forces, such as oncogenes and suppressors of oncogenes. Examples of this are provided by the genetic regulation of metastasis, involving metalloproteinase as well as the inhibitor of metalloproteinase. The immortalization of cells by transformation points to the fact that programmed cell death and the balance between suicide genes and suppressors of such suicide genes is affected.
 ...
PMID:Evolutionary aspects of human cancer. 130 36

Lymphocytes are particularly susceptible to DNA damage-induced apoptosis, a response which may serve as a form of 'altruistic suicide' to counter their intrinsic high potential for mutation and clonal expansion. The tumour suppressor p53 has been shown to regulate this type of apoptosis in thymocytes, but an as yet unknown, p53-independent pathway(s) appears to mediate the same event in mitogen-activated mature T lymphocytes. Here we show DNA damage-induced apoptosis in these T lymphocytes is dependent on the antioncogenic transcription factor interferon regulatory factor (IRF)-1. Thus two different anti-onco-genic transcription factors, p53 and IRF-1, are required for distinct apoptotic pathways in T lymphocytes. We also show that mitogen induction of the interleukin-1 beta converting enzyme (ICE) gene, a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, is IRF-1-dependent. Ectopic overexpression of IRF-1 results in the activation of the endogenous gene for ICE and enhances the sensitivity of cells to radiation-induced apoptosis.
 ...
PMID:An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes. 763 9

Apoptosis is an evolutionarily conserved 'suicide' programme present in all metazoan cells. Despite its highly conserved nature, it is only recently that any of the molecular mechanisms underlying apoptosis have been identified. Several lines of reasoning indicate that apoptosis and cell proliferation coincide to some degree: many oncogenes that promote cell cycle progression also induce apoptosis; damage to the cell cycle or to DNA integrity is a potent trigger of apoptosis; and the key tumour suppressor proteins, p105rb and p53, exert direct effects both on cell viability and on cell cycle progression. There is less evidence, however, to indicate that apoptosis and the cell cycle share common molecular mechanisms. Moreover, the interleukin-1 beta converting enzyme (ICE) family of cysteine proteases is now known to play a key role in apoptosis but has no discernible role in the cell cycle, arguing that the two processes are discrete.
 ...
PMID:Apoptosis and the cell cycle. 860 13

Prostate cancer is one of the leading causes of cancer deaths in the Western world and current therapies are of limited efficacy in advanced disease. Both ex vivo and in vivo gene therapy strategies offer exciting new possible approaches to the management of this disease. Ex vivo gene therapy involving interleukin-2 or granulocyte-macrophage colony-stimulating factor transduced whole tumour cell vaccines has shown great promise in animal models. The feasibility of in vivo corrective gene therapy involving the replacement of mutant tumour suppressor genes, antisense strategies and the insertion of suicide genes has been demonstrated in preclinical models. Several of these therapies are now entering phase I/II studies in patients with prostate cancer.
 ...
PMID:Gene therapy for prostate cancer. 890 97

Extensive research has led to accumulation of common hereditary evidence concerning ovarian and breast cancer, suggesting that these two cancers can be considered as one type. Subsequently, women with breast cancer are susceptible to the risk of developing ovarian cancer. Highly expressed oncogenes such as bcl-2, HER2/neu and others or mutated suppressor genes such as p53 or BRCA1 have been characterised as hereditary susceptibility genes leading to syndromes such as breast/ovarian cancer syndrome, Li-Fraumeni and others. Furthermore, these genetic alterations can cause potent chemoresistance by inhibiting induction of apoptosis after DNA damage caused by chemotherapy and/or radiotherapy. Presently, molecular onco-biology has enabled us not only to detect susceptibility to ovarian and breast cancer but also ways to inhibit their further progression or even circumventing chemoresistance mechanisms after their development by gene therapy using delivery vectors such as liposomes or viruses, by which we can replace wild-type tumour suppressor genes or by using antigene, antisense oligonucleotides and antisense RNA leading to reduced oncogene expression, enabling induction of apoptosis after DNA damage into chemoresistant tumour cells. Furthermore efflux-genes such as MDR-1 or MRP can be circumvented, suicide-genes can be employed which can facilitate sensitivity by encoding enzymes capable of converting inactive forms of a drug into toxic antimetabolites and immunotherapy can be achieved, by transfection of tumour cells with adenoviral vectors encoding immunomodulators such as IL-2 or MHC molecules. Thus, molecular biology appears to be a very strong element for the screening, diagnosis, therapy and prognosis of ovarian and breast cancer. However, consistent future research is greatly needed because many points concerning ovarian and breast cancer genetics are still unknown. Finally, we strongly believe that gene therapy could be extremely useful when is combined with conventional therapy against ovarian and breast tumours.
 ...
PMID:Molecular aspects of breast and ovarian cancer. 937 59

Our understanding of the molecular genetics of pancreatic cancer has advanced spectacularly over the last 5 years so that this tumour type is now one of the best characterised of all malignancies. A small proportion of cases results from inherited predisposition due to germline transmission of a mutated CDKN2 or BRCA2 gene, while patients with familial pancreatitis due to a mutated cationic trypsinogen gene have a greatly increased risk of developing pancreatic cancer. The majority of cases are sporadic and are characterised at the molecular level by several key genetic abnormalities. The most frequent of these is point mutation of the dominant oncogene KRAS, a lesion which occurs as an early and possibly initiating event in tumourigenesis. Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis. Genetic intervention for cancer prevention and therapy is becoming a clinical reality and several approaches are being pursued for pancreatic cancer. As well as tumour suppressor gene replacement and oncogene blockade, strategies with a potential bystander effect are showing promise. These include genetic prodrug activation therapy using selective expression of suicide genes and genetic immunomodulation with cytokines and tumour-associated antigens.
 ...
PMID:Molecular advances in pancreatic cancer. 943 1

Programmed cell death or apoptosis is an active physiological process that permits the removal of unwanted or damaged cells from the body through an intrinsic cell-suicide program. Apoptosis is characterized by condensation of the nucleus and cytoplasm without loss of membrane integrity. The occurrence of apoptosis in the vasculature and myocardium has recently been described. Inappropriate loss of myocardial cells is suggested to contribute to conduction defects and ventricular remodelling after injury. The molecular mechanisms that regulate programmed cell death in cardiac muscle cells are poorly defined. However, recent evidence has suggested that specific genes can either provoke or prevent apoptosis. In this regard, the tumour suppressor protein p53 has been proposed to mediate apoptosis, while the Bcl-2 protein prevents it. Prevention of apoptosis in the heart is potentially of significant therapeutic value given the limited capacity of the heart to repair itself after injury. This study determined that the expression of p53 in ventricular myocytes is sufficient to trigger apoptosis. Moreover, p53 results in a significant increase in the expression of the death-promoting protein Bax. Importantly, the antiapoptotic factor Bcl-2 is sufficient to prevent p53-mediated apoptosis and p53-dependent transcription of Bax in ventricular myocytes. The data substantiate a role for p53 and Bcl-2 as crucial regulators of apoptosis in the heart.
 ...
PMID:Regulators of apoptosis in the heart: a matter of life and death. 955 Oct 35

The majority of human anogenital carcinomas show evidence of papillomavirus infection. To facilitate viral replication, viruses disable key cellular responses which would otherwise precipitate cell suicide. An obligate factor in one such response is the p53 tumour suppressor protein. p53 gene mutation is an infrequent event in anogenital cancer, apparently due to the action of HPV E6 protein, which inhibits wild-type p53 function by stimulating the degradation of p53 protein. p53 is required for the apoptotic response that is triggered in untransformed cells following inappropriate cell-cycling. E6 directed inhibition of p53 function thus facilitates the survival of transformed cells. We have developed a genetically tractable model that reports E6 protein-mediated human p53 inactivation in the fission yeast Schizosaccharomyces pombe. Functional dissection of the requirements for E6 directed inhibition in this system reveal an absolute requirement for the presence of both E6 protein and the human E3 ubiquitin ligase, E6-AP. Using a defined set of E6 mutants we show that degradation of p53 protein rather than E6/p53 association is likely required for E6-mediated inhibition. This S. pombe based system represents a candidate screen for novel antiviral agents that act by disrupting the E6/E6-AP/p53 interaction.
 ...
PMID:Defining the minimal requirements for papilloma viral E6-mediated inhibition of human p53 activity in fission yeast. 958 24

Each cell is under constant surveillance to maintain the integrity of its genome. Genomic lesions in a cell must be repaired before the onset of DNA replication and cell division. In the scenario that the genomic lesion is not repairable, the damaged cells are disposed in an orderly manner known as programmed cell death or apoptosis. Apoptosis and cell cycle progression are two intimately linked phenomena. Uncontrollable cell proliferation perturbs the cellular homeostasis and this can lead to malignancies, as well as organ dysfunction and developmental abnormalities. The biological pathway controlling cell fate is sequentially organized at the molecular level. Recent studies have made important contributions in advancing our knowledge of the mechanisms of cell cycle control and apoptosis regulation. A oncogene-derived protein, Bcl2, confers negative control in the pathway of cellular suicide machinery. A Bcl2-homologous protein, Bax, promotes cell death by competing with Bcl2. While Bax-Bax homodimers act as apoptosis inducers, Bcl2-Bax heterodimer formation evokes a survival signal for the cells. Both Bcl2 and Bax are transcriptional targets for the tumour suppressor protein, p53, which induces cell cycle arrest or apoptosis in response to DNA damage. In all, the coordinate performance of these molecules is crucial for controlling life and death of a cell.
 ...
PMID:The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death. 987 59

Advances in our understanding of the molecular genetics of pancreatic and biliary cancers have given us new targets for therapy using molecular and genetic approaches. Replacement of tumour suppressor gene function using adenoviruses to transfer wild-type p53 and p16 genes can produce dramatic anti-tumour effects, both in vitro and in vivo. Blockade of dominant oncogene function using dominant negative technology may have a particular application for mutated K-ras which occurs almost ubiquitously in pancreatic adenocarcinoma. Genetic prodrug activation therapy using tumour-selective gene promoters to drive the expression of so-called suicide genes is showing remarkable promise. Targeted delivery of such therapeutic constructs may also be possible through knowledge of the expression of surface receptors by particular tumour cell types. Genetic immunomodulation using cytokine genes as well as specific vaccines against tumour-associated antigens are now being brought into clinical trials.
 ...
PMID:Gene therapy for pancreatic and biliary malignancies. 1043 19


1 2 3 Next >>