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)

p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes, and is a negative regulator of cell proliferation. The gene encoding human p57KIP is located on chromosome 11p15.5 (ref. 2), a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome, marking it a tumour suppressor candidate. Several types of childhood tumours including Wilm's tumour, adrenocortical carcinoma and rhabdomyosarcoma display a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting plays an important part. Genetic analysis of the Beckwith-Wiedemann syndrome has indicated maternal carriers as well as suggested a role in genomic imprinting. Here, as a first step towards elucidating the genesis of human cancers in this region, we showed that a mouse homologue of p57KIP2 is genomically imprinted. The paternally inherited allele is transcriptionally repressed and methylated. This murine gene maps to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-2, insulin-like growth factor-2, H19 and Mash2 (refs 14-18).
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PMID:Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. 755 Mar 51

Growth factors, such as insulin, EGF, PDGF, are indispensable elements of the regulation of cell proliferation. In the last years signal transduction pathways of many growth factors have been elucidated. p21 ras, a proto-oncogene product, plays a central role in growth signalling. The medical importance of the investigation of Ras proteins comes from the fact that mutant forms of Ras genes were found in a number of human tumours. The review summarizes the signal transduction pathways of growth factors, with special respect to the connection of protooncogenes, tumour suppressor genes and cancer research.
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PMID:[Oncogenes and tumor suppressor genes in the signal transduction pathways of growth factors]. 782 56

Proto-oncogenes, growth factors/receptors, and tumour suppressor genes were analysed in malignant metastatic insulinomas. Normal pancreas showed only a moderate immunoreaction for c-myc proto-oncogene and a strong reaction for insulin. Benign insulinomas were slightly or moderately positive for transforming growth factor alpha (TGF alpha), weakly positive for epidermal growth factor receptor (EGF-R), and strongly positive for c-myc and insulin. In malignant insulinomas, besides a strong immunoreaction for c-myc and TGF alpha, activation of c-K-ras and overexpression of p53 protein were found. Insulin reaction was moderate or strong. Three out of six malignant insulinomas displayed a c-K-ras point mutation at codon 12. All mutations were guanine to cytosine transversion, resulting in amino acid substitution, glycine to arginine. Mutations were present in metastatic insulinomas only. Patients with mutated c-K-ras oncogene had overexpression of p53 protein as well as c-myc and TGF alpha overexpression. Our results support the view that malignant progression is a consequence of more than one genetic lesion and suggest that activation of myc, TGF alpha an ras genes plays a role in a multistep process of tumour progression, perhaps serving as an initiating event.
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PMID:Multiple genetic alterations in malignant metastatic insulinomas. 856 94

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

The tumour suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancer types [1] [2] [3] [4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN encodes a dual-specificity phosphatase that inhibits cell spreading and migration partly by inhibiting integrin-mediated signalling [5] [6] [7]. Furthermore, PTEN regulates the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring [8]. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. Others have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild-type daf-18 transgene rescues the dauer defect. These results indicate that PTEN/daf-18 antagonizes the DAF-2-AGE-1 pathway, perhaps by catalyzing dephosphorylation of the PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI 3-kinase signalling cascade.
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PMID:Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. 1020 98

Insulin-like growth factors (IGF) are mitogenic peptides that have been implicated as positive regulators of cellular proliferation. In recent years, several studies have suggested an additional role for the IGF axis in the regulation of apoptosis. Signalling through the IGF receptor has been shown to have a potent survival function and protect cells from a variety of apoptotic stimuli. The actions of IGF are regulated by a family of high-affinity IGF binding proteins (IGFBP), which sequester the IGF from the IGF receptor. However, there is some evidence that one of these binding proteins, IGFBP-3, may have its own pro-apoptotic effects that are independent of its ability to modulate IGF bioavailability. In addition, it has been suggested that the tumour suppressor p53, a crucial mediator of apoptosis in response to cellular stress, may elicit several of its apoptotic effects through manipulation of components of the IGF axis. This review summarizes what is currently known about the role of the IGF system in the regulation of apoptosis, highlighting its implications in the context of tumorigenesis.
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PMID:The IGF axis and programmed cell death. 1036 Dec 58

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a heterogeneous disorder characterized by profound hypoglycaemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI), because the management differs significantly. The intriguing similarity between islet cell hyperplasia and tumourigenesis prompted us to investigate whether the imprinted genes in the 11p15 region are involved. Results showed that diffuse forms are caused by constitutional homozygous or compound heterozygous mutations of the SUR1 gene. In contrast, focal forms are caused by loss of the maternally inherited 11p15 region, resulting in both loss of the maternally expressed tumour suppressor genes accounting for hyperplasia and somatic reduction to hemizygosity or homozygosity of the paternally inherited SUR1, limited to the lesion. Thus, this somatic disorder, which leads both to beta-cell proliferation and to hyperinsulinism, can be considered the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation.
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PMID:Loss of imprinted genes and paternal SUR1 mutations lead to focal form of congenital hyperinsulinism. 1089 35

The tumour suppressor gene PTEN/MMAC1/TEP1 encodes a dual-specificity phosphatase that recognizes phosphatidylinositol-3,4,5-triphosphate and protein substrates. We have shown previously that over-expression of PTEN in a tetracycline-controlled inducible system blocks cell cycle progression and induces apoptosis in MCF-7 breast cancer cells. Here, we demonstrate that over-expression of wild-type PTEN leads to the suppression of cell growth through the blockade of cell cycle progression, an increase in the abundance of p27, a decrease in the protein levels of cyclin D1 and the inhibition of Akt phosphorylation. In contrast, expression of the phosphatase-dead mutant, C124S, promotes cell growth and has the opposite effect on the abundance of p27, cyclin D1 levels and the phosphorylation of Akt. The G129E mutant, which does not have lipid phosphatase activity but retains protein phosphatase activity, behaves like C124S except that the former causes decreases in cyclin D1 levels similar to wild-type PTEN. Therefore, PTEN exerts its growth suppression through lipid phosphatase-dependent and independent activities and most likely, via the coordinate effect of both protein phosphatase and lipid phosphatase activities. Addition of either estrogen or insulin abrogates PTEN-mediated up-regulation of p27 and partially blocks PTEN-mediated growth suppression, whereas the combination of estrogen and insulin eliminates the alterations of p27 and cyclin D1 and completely blocks PTEN-mediated growth suppression. Our findings demonstrate that PTEN blocks cell cycle progression differentially through down-regulating the positive cell cycle regulator, cyclin D1, by its protein phosphatase activity, and up-regulating the negative cell cycle regulator, p27, by its lipid phosphatase activity.
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PMID:PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. 1123 Jan 79

The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein substrates and phosphatidylinositol-3,4,5-triphosphate. PTEN seems to play multiple roles in tumour suppression and the blockade of phosphoinositide-3-kinase signalling is important for its growth suppressive effects, although precise mechanisms are not fully understood. In this study, we show that PTEN plays a unique role in the insulin-signalling pathway in a breast cancer model. Ectopic expression of wild-type PTEN in MCF-7 epithelial breast cancer cells resulted in universal inhibition of Akt phosphorylation in response to stimulation by diverse growth factors and selective inhibition of MEK/extracellular signal-regulated kinase (ERK) phosphorylation stimulated by insulin or insulin-like growth factor 1 (IGF-1). The latter was accompanied by a decrease in the phosphorylation of insulin receptor substrate 1 (IRS-1) and the association of IRS-1 with Grb2/Sos, without affecting the phosphorylation status of the insulin receptor and Shc, nor Shc/Grb2 complex formation. The MEK inhibitor, PD980059, but not the PI3K inhibitor, wortmannin, abolished the effect of PTEN on insulin-stimulated cell growth. Without addition of insulin, wortmannin reduced PTEN-mediated growth suppression, whereas PD980059 had little effect, suggesting that PTEN suppresses insulin-stimulated cell growth by blocking the mitogen-activated protein kinase (MAPK) pathway. Furthermore, PD980059 treatment led to the downregulation of cyclin D1 and the suppression of cell cycle progression. Our data suggest that PTEN blocks MAPK phosphorylation in response to insulin stimulation by inhibiting the phosphorylation of IRS-1 and IRS-1/Grb2/Sos complex formation, which leads to downregulation of cyclin D1, inhibition of cell cycle progression and suppression of cell growth.
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PMID:PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. 1123 Jan 80

PtdIns(3,4,5)P3 is an established second messenger of growth-factor and insulin-induced signalling pathways. There is increasing evidence that one of the immediate breakdown products of PtdIns(3,4,5)P3, namely PtdIns(3,4)P2, whose levels are elevated by numerous extracellular agonists, might also function as a signalling molecule. Recently, we identified two related pleckstrin-homology (PH)-domain-containing proteins, termed 'tandem-PH-domain-containing protein-1' (TAPP1) and TAPP2, which interacted in vitro with high affinity with PtdIns(3,4)P2, but did not bind PtdIns(3,4,5)P3 or other phosphoinositides. In the present study we demonstrate that stimulation of Swiss 3T3 or 293 cells with agonists that stimulate PtdIns(3,4)P2 production results in the marked translocation of TAPP1 to the plasma membrane. This recruitment is dependent on a functional PtdIns(3,4)P2-binding PH domain and is inhibited by wortmannin, a phosphoinositide 3-kinase inhibitor that prevents PtdIns(3,4)P2 generation. A search for proteins that interact with TAPP1 identified the multi-PDZ-containing protein termed 'MUPP1', a protein possessing 13 PDZ domains and no other known modular or catalytic domains [PDZ is postsynaptic density protein (PSD-95)/Drosophila disc large tumour suppressor (dlg)/tight junction protein (ZO1)]. We demonstrate that immunoprecipitation of endogenously expressed TAPP1 from 293-cell lysates results in the co-immunoprecipitation of endogenous MUPP1, indicating that these proteins are likely to interact with each other physiologically. We show that TAPP1 and TAPP2 interact with the 10th and 13th PDZ domain of MUPP1 through their C-terminal amino acids. The results of the present study suggest that TAPP1 and TAPP2 could function in cells as adapter proteins to recruit MUPP1, or other proteins that they may interact with, to the plasma membrane in response to signals that elevate PtdIns(3,4)P2.
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PMID:Evidence that the tandem-pleckstrin-homology-domain-containing protein TAPP1 interacts with Ptd(3,4)P2 and the multi-PDZ-domain-containing protein MUPP1 in vivo. 1180 82


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