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)

C-CAMs are epithelial cell-adhesion molecules of the immunoglobulin supergene family with sequences highly homologous to carcinoembryonic antigen (CEA). C-CAMs and their human homologues, biliary glycoproteins, are unique among the CEA-family proteins in that they have cytoplasmic domains. Furthermore, alternative splicing generates C-CAM isoforms with different cytoplasmic domains, suggesting that the cytoplasmic domains of C-CAM may play important roles in regulating the function or functions of C-CAM. By using both sense and antisense approaches, we have shown that C-CAM1 is a tumour suppressor in prostate carcinogenesis. This observation raises the possibility that the cytoplasmic domain of C-CAM1 may be involved in signal transduction or interaction with cytoskeletal elements to elicit the tumour suppressor function. The cytoplasmic domain of C-CAM1 contains several potential phosphorylation sites, including putative consensus sequences for cyclic AMP-dependent kinase and tyrosine kinase. One of the potential tyrosine phosphorylation sites is located within the antigen-receptor homology (ARH) domain. The ARH domain of the membrane-bound IgM molecule is necessary for signal transduction in B-cells. These structural features suggest that the cytoplasmic domain of C-CAM1 may be important for signal transduction. To test this possibility, we generated several site-directed C-CAM1 mutants and tested their ability to support adhesion and their abilities to be phosphorylated in vivo. Results from these studies revealed that Tyr-488 is phosphorylated in vivo. However, replacing this tyrosine with phenylalanine did not significantly compromise its adhesion function. Similarly, Ser and Thr residues are phosphorylated in vivo, but deletion of the potential cyclic AMP-dependent kinase site did not significantly reduce the adhesion function. These results suggest that the kinase phosphorylation sites in the cytoplasmic domain of C-CAM1 are not required for the adhesion function. However, these phosphorylation sites are probably involved in the regulation of C-CAM-mediated signal transduction. Thus, there are probably distinct structural requirements for the adhesion and the signal transduction functions of C-CAM. Incidentally, a C-CAM1 deletion mutant containing a 10-amino-acid cytoplasmic domain was able to support adhesion activity. This is in contrast to our previous finding that a C-CAM isoform, C-CAM3, with a 6-amino-acid cytoplasmic domain could not support cell adhesion. This result indicates that the extra four amino acids, which are absent in C-CAM3 and contain a potential Ser/Thr phosphorylation site, are important for the adhesion function.
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PMID:Structure and function of C-CAM1: effects of the cytoplasmic domain on cell aggregation. 757 60

The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 receptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.
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PMID:Mechanisms and pathogenesis of thyroid cancer in animals and man. 853 19

Chronic myeloid leukaemia (CML) is characterized cytogenetically by a t(9;22)(q34;ql1) reciprocal translocation which gives origin to a hybrid BCR-ABL gene, encoding a p2lO(BCR-ABL) fusion protein with elevated tyrosine kinase activity and transforming abilities. The t(9;22) was suggested to be associated with genomic imprinting of centromeric regions of chromosomes 9 and 22, but the genes directly affected by the translocation, ABL and BCR, were shown not to be imprinted. For most diagnostic and research purposes the BCR-ABL gene can be efficiently identified by reverse-transcription and polymerase chain reaction (RT/PCR) amplification of its fusion transcripts, which can be quantified by competitive PCR and similar assays for assessment of residual disease in the follow-up of therapy. In the great majority of CML patients the BCR-ABL transcripts exhibit a b2a2 and/or a b3a2 junction; in rare cases, the only detectable BCR-ABL transcripts have unusual junctions, such as b2a3, b3a3, e1a2 or e6a2. There is a recent suggestion that the BCR-ABL gene may not be always 'functional', since extremely low levels of BCR-ABL transcripts can be found in leucocytes from normal individuals and, conversely, it appears that no BCR-ABL transcription can be detected in a proportion of Ph-positive haematopoietic progenitors from some CML patients. The role, if any, of the reciprocal ABL-BCR hybrid gene in CML is unknown. Although its mRNA message is in frame, no ABL-BCR fusion protein has yet been identified in CML patients. The blast crisis of CML has been variably associated with abnormalities of proto-oncogenes, such as RAS and MYC, or of tumour suppressor genes, in particular RB, p53 and p16, or with the generation of chimeric transcription factors, as in the AML1-EVI1 gene fusion. It is likely, therefore, that multiple and alternative molecular defects, as opposed to a single universal mechanism, underlie the acute transformation of the disease.
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PMID:The molecular biology of chronic myeloid leukaemia. 865 67

The last five years have seen a rapid increase in interest and understanding of signal transduction pathways. While the description of such pathways has become more detailed and complex, a number of consistent findings have emerged. Modular domains, such as SH2 and SH3 domains, are present on a wide variety of proteins and mediate specific protein-protein interactions. By defining the interaction mediated by such domains, a 'language' of interaction between proteins in signalling pathways is emerging. As more signalling proteins are identified it has become apparent that most oncogenes and tumour suppressor genes are components of major signalling pathways. Therefore, studies on the basic biology of signal transduction are having a direct impact on our understanding of cell transformation. With the characterisation of signalling pathways in a range of organisms, it has also become obvious that signalling pathways are ancient and have been highly conserved over the last billion years of evolution. A practical result of this finding has been the ability to exploit results obtained in genetically tractable invertebrate species such as C. elegans and Drosophila melanogaster to investigate signal transduction in mammals. This is an approach we have emphasized in our investigation of signal transduction by tyrosine kinase receptors in human and mouse cells. Results obtained in these studies with the Sos and Siah proteins are reviewed.
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PMID:A combined genetic and biochemical approach to mammalian signal transduction. 877 Mar 62

Carcinoid tumours may develop from enterochromaffin cells in the gastrointestinal tract. Benign insulin-producing tumours may develop from islet cells, whereas other islet cell tumours might derive from multipotent stem cells in the pancreatic ducts. The idea that multiple endocrine neoplasia type 1 (MEN-1) tumours in the pancreas originate from multipotent stem cells is supported by our demonstration that CD44 is expressed in exocrine cells, in gastrin-producing endocrine cells only and in some non-functioning islet cell tumours; there are no gastrin-producing cells in the adult pancreas. We have identified phospholipase C beta 3 (PLC beta 3) as the gene implicated in MEN-1. It appears to be a tumour suppressor gene since it is expressed in endocrine pancreatic tumours, some lung carcinoids, and medullary thyroid carcinomas. So neuroendocrine tumours might have a dual growth-regulating system, involving both traditional growth factors through the tyrosine kinase system and also G-protein-mediated growth signals. Deletion of PLC beta 3, which is an important enzyme in the signal transduction pathway of G-protein-mediated signals, might be important in the growth regulation of neuroendocrine tumours. It is proposed that its deletion causes dysregulation of growth control in neuroendocrine cells, with possible distortion of the apoptotic process. In the last stage of the disease, tumour biology is altered and becomes more aggressive. Further, chromogranin A may be both a tumour marker for neuroendocrine tumours and a growth-promoting agent for neuroendocrine tumour cells; it is a very good marker of tumour mass but is also related to poor prognosis of survival. Mutation analyses of PLC beta 3 and studies of the growth-promoting effect of chromogranin are ongoing and should lead to more effective therapies.
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PMID:Biological aspects of neuroendocrine gastro-enteropancreatic tumours. 881 67

Breast cancer is the commonest malignancy in women and although identification of this multi-system disease has increased, the survival rates have not dramatically altered over the past four decades. Optimium treatment of patients with breast cancer is a subject of great debate and traditionally may be divided into surgery, radiotherapy, chemotherapy and hormone manipulation. Halsted's radical mastectomy, although initially superseded by more mutilating surgery involving removal of tumour, breast, pectoral muscles and axillary contents, has given way to more conservative surgery and breast conservation, so now removal of the tumour with a marginal of healthy tissue is possible. Additional loco-regional radiotherapy has added to the increasing number of treatment options available to both doctor and patient. Systemic adjuvant therapy, primarily hormonal therapy, is used with the aim of decreasing the incidence of recurrence and distant tumour development. Through the process of randomized controlled trials these new therapeutic treatments have shown to be effective in the treatment of locoregional disease. Surgery in patients with advanced systemic disease is limited, however radiotherapy is of considerable importance and can be used to treat or palliate sites of metastases. In recent years trials have assessed chemotherapeutic regimens. However, limited number of patients and adequate randomization have hindered the confident acceptance of these results. Cyclophosphamide, methotrexate and 5 fluorouracil still remain the standard chemotherapeutic regimen, however many new drugs are currently undergoing trials and these or combinations of these may prove to be of future clinical use. Dramatic advances in cell and molecular biology have allowed the development of novel breast cancer therapies. Specific oncogenes and loss of tumour suppressor genes have been associated with decrease patient survival, with the presence of lymph node metastases and with decreased relapse free survival. Growth factor receptor blockers and tyrosine kinase inhibitors may be developed to specifically eradicate breast cancer cells. Immunotherapy and gene therapy may produce effective therapies. Trials utilizing cytokines and trials increasing the immunogenicity of tumours have already reported promising results. Surgery, chemotherapy, radiotherapy and hormone manipulation are the major treatment arms of breast cancer therapy. However, breast cancer still accounts for 20 percent of all female cancer deaths and the overall survival of patients has remained relatively static over the past forty years. From our increasing understanding of the pathological processes involved in the development and spread of breast cancer, new pharmaceutical, immunological and gene therapies may dramatically increase the cure rate of this serious disease.
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PMID:The increasing efficacy of breast cancer treatment. 936 31

The p53 tumour suppressor phosphoprotein associates with proteins involved in DNA replication, transcription, cell cycle machinery and regulation of its own expression. Recently it has been shown that p53 can also bind to trk A tyrosine kinase which is the receptor for nerve growth factor (NGF). This study demonstrates that p53 appears to associate with trk A via c-abl. Endogenous c-abl was detected when the trk A and p53 complex was immunoprecipitated from lysates of NGF stimulated NIH3T3 cells expressing trk A or NIH3T3 cells expressing trk A and a temperature sensitive p53 (val 135). Endogenous c-abl and trk A association was observed in NGF stimulated p53 negative fibroblasts transfected with trk A alone; suggesting that c-abl can independently bind to trk A in the absence of p53. Interestingly, association between endogenous p53 and trk A was not detected in NGF stimulated abl negative fibroblasts transfected with trk A or when these cells were exposed to gamma radiation. This result suggests that p53 preferentially binds to trk A in the presence of c-abl and that p53 and trk A do not appear to associate directly even if p53 is activated and its levels increased by gamma radiation. Overall, these data suggest that c-abl is possibly acting as an adaptor or bridge between p53 and trk A. Oncogene (2000).
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PMID:c-abl is involved in the association of p53 and trk A. 1087 55

trk A tyrosine kinase (the high affinity receptor for nerve growth factor) binds to the p53 tumour suppressor protein in vitro and in vivo. Our aim was to determine which regions of p53 are involved in trk A association. In vitro binding experiments using baculovirus expressed trk A and in vitro transcribed and translated C-terminus p53 deletion mutants show amino acids 327-338 critical for association. Also, analysis with mutants at the N-terminus, conserved regions II, III, IV and V or amino acid positions 173, 175, 181, 248 and 249 (which are amino acids frequently mutated in a variety of neoplasms and transformed cell lines), show that these sites are not involved in trk A binding. Importantly, similar results are obtained after immunoprecipitation of lysates from p53 negative fibroblasts expressing trk A and the above p53 mutant proteins. These data suggest that the amino-terminus of the oligomerisation domain of p53 is involved in p53/trk A association.
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PMID:Analysis of trk A and p53 association. 1137 56

The choice between growth arrest and apoptosis is made during differentiation, leading to survival with permanent arrest (e.g. neurons), or to death (e.g. epithelium). Genotoxic stress can also cause growth arrest or apoptosis, in addition to the activation of cell cycle checkpoint pathways. The p53 tumour suppressor can simulate growth arrest and apoptosis in response to DNA damage. Thus, p53 alone is not sufficient to specify these two mutually exclusive fates in damaged cells. The retinoblastoma tumour suppressor protein (RB) is a necessary downstream effector in p53-mediated growth arrest. RB inhibits E2F and the nuclear c-Abl tyrosine kinase. Interestingly, E2F activates the transcription of p73 mRNA and c-Abl stabilizes the p73 protein and activates its pro-apoptotic function. Because of RB, the c-Abl/p73 apoptosis pathway is activated in S/G(2) cells but not in G(1) cells. Taken together, the current data suggests RB to be an important player in directing the choice between permanent arrest and apoptosis. The antagonism between RB and c-Abl/p73 may modulate the function of p53 to direct the choice between growth arrest and apoptosis in DNA damaged cells.
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PMID:Choosing between growth arrest and apoptosis through the retinoblastoma tumour suppressor protein, Abl and p73. 1170 51

Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in effect, gave OSI a royalty-free, cashless license to the drug. In November 2001, OSI announced a partnership deal with HopeLink Corporation, a healthcare information technology company with an Internet-based Clinical Trial Service. The partnership will enable OSI to heighten awareness of its clinical trials and shorten patient accrual times. It will initially involve the presentation of the OSI phase III pancreatic and refractory NSCLC trials via Hopelink's Syndicated Network. In addition to this the two companies have also agreed to develop additional products and service together that will increase the efficiency of the clinical trial process, increase awareness of clinical trials, and enhance patient accrual techniques. OSI has also entered into an agreement with Therradex, a contract research organisation (CRO) to monitor phase II trials for erlotinib in NSCLC, ovarian and head and neck cancer. In addition, OSI entered into an agreement in 2001 with the US NCI. The NCI is conducting trials in a variety of different cancers. A phase III front-line NSCLC trial (TRIBUTE) of erlotinib in combination with carboplatin and paclitaxel was initiated in July 2001. The multicentre study is being conducted by Genentech in 1000 patients in the US, and will determine whether the addition of erlotinib to carboplatin chemotherapy is able to improve the duration of patient survival. Enrolment for this trial was completed in July 2002. An independent Data Monitoring Committee (DMC) has since reviewed the data from the trial and concluded that there are no safety or efficacy concerns that would warrant stopping the trial. However, the DMC did recommend stopping erlotinib at the time of disease progression or at the start of second-line therapy. A front-line phase III study of erlotinib in NSCLC (TALENT) in combination with gemcitabine and cisplatin chemotherapy was initiated by Roche in Europe in November 2001. Enrolment into this study was completed in September 2002, with approximately 1200 patients. Roche has confirmed that the study woulde has confirmed that the study would be included in the alliance's potential regulatory submission for front-line therapy in chemotherapy-naive patients in the US. Data from the trial is expected in the second half of 2003. OSI has opened two additional phase Ib studies to examine the potential of erlotinib in combination with carboplatin and paclitaxel in one study and gemcitabine and cisplatin in the other. A phase I study of erlotinib is also being conducted in patients with lung cancer in Japan. OSI received fast-track status from the US FDA in September 2002 for erlotinib as a second- or third-line treatment for patients with incurable stage IIIB/IV NSCLC who have failed to respond to standard therapy for advanced metastatic disease. Fast-track status was also granted to erlotinib in May 2002 for the treatment of chemotherapy-naive stage III/IV NSCLC. There are important differences between phase III studies of erlotinib and AstraZeneca's direct competitor drug gefitinib, which recently returned disappointing results in a frontline NSCLC trial with combination chemotherapy. In assessing the survival benefit of erlotinib with chemotherapy, the dose employed of 150 mg/day is the maximum tolerated dose (MTD), whereas the gefitinib trials were conducted at relatively lower doses than the MTD determined in earlier phase I studies. OSI is also investigating the survival benefit of erlotinib in a phase III study in refractory NSCLC patients, a key registration study. Patient size of the NSCLC trial was increased from 330 to 700 as OSI shifted emphasis from its pancreatic cancer trials. Phase II development for this indication was initiated based on data from a phase I trial, which had completed patient enrolment by April 2003. OSI and the US NCI signed a collaborative research agreement in 2001. The NCI is developing erlotinib through its CTEP programme for multiple tumour types including epithelial malignancies, gastrointestinal and genitourinary tracts, gynaecological malignancies and brain tumours. OSI supplies erlotinib for the trial, but the NCI provides the funding and manages the trials. A series of approximately ten phase Ib trials are already underway or were set to start in the US in 2001 to determine safety, tolerance and pharmacokinetic parameters of erlotinib in combination with a number of commonly used chemotherapeutic agents. The Wall Street Journal reported on 25 February 2002, that analysts at Robert Stephens, New York, USA, have forecast Tarceva to reach annual sales of >$US1 billion. Other analysts, at Merrill Lynch & Co., have predicted that products belonging to the same class as Tarceva could reach combined worldwide sales of $US6 billion to $US10 billion annually. In an earlier report by the Financial Times on 10 May 2001, it was stated that approximately 12 new anticancer agents are expected to be approved by the FDA through to the end of 2002. These agents, of which Tarceva is one, were said to have the potential to generate total sales of $US2.6 billion. Goldman Sachs have forecast Tarceva to reach peak sales of $US250 million for the indication of head and neck cancer alone. Previously in January 2001, the Financial Times claimed that OSI Pharmaceuticals, one of the development partners for Tarceva, stood to gain $US187 million pending regulatory approval. Genentech and Roche were each said to be buying $US35 million worth of OSI's stock and paying upfront fees. Tarceva is facing competition by two similar compounds, developed by AstraZeneca and ImClone, respectively.
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PMID:Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415. 1284 90


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