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)

It has been postulated that PtdIns(3,4) P (2), one of the immediate breakdown products of PtdIns(3,4,5) P (3), functions as a signalling molecule in insulin- and growth-factor-stimulated pathways. To date, the t andem- P H-domain-containing p rotein- 1 (TAPP1) and related TAPP2 are still the only known PH-domain-containing proteins that interact strongly and specifically with PtdIns(3,4) P (2). In this study we demonstrate that endogenously expressed TAPP1, is constitutively associated with the protein-tyrosine-phosphatase-like protein-1 (PTPL1 also known as FAP-1). We show that PTPL1 binds to TAPP1 and TAPP2, principally though its first PDZ domain [where PDZ is postsynaptic density protein ( P SD-95)/ Drosophila disc large tumour suppressor ( d lg)/tight junction protein ( Z O1)] and show that this renders PTPL1 capable of associating with PtdIns(3,4) P (2) in vitro. Our data suggest that the binding of TAPP1 to PTPL1 does not influence PTPL1 phosphatase activity, but instead functions to maintain PTPL1 in the cytoplasm. Following stimulation of cells with hydrogen peroxide to induce PtdIns(3,4) P (2) production, PTPL1, complexed to TAPP1, translocates to the plasma membrane. This study provides the first evidence that TAPP1 and PtdIns(3,4) P (2) could function to regulate the membrane localization of PTPL1. We speculate that if PTPL1 was recruited to the plasma membrane by increasing levels of PtdIns(3,4) P (2), it could trigger a negative feedback loop in which phosphoinositide-3-kinase-dependent or other signalling pathways could be switched off by the phosphatase-catalysed dephosphorylation of receptor tyrosine kinases or tyrosine phosphorylated adaptor proteins such as IRS1 or IRS2. Consistent with this notion we observed RNA-interference-mediated knock-down of TAPP1 in HEK-293 cells, enhanced activation and phosphorylation of PKB following IGF1 stimulation.
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PMID:Interaction of the protein tyrosine phosphatase PTPL1 with the PtdIns(3,4)P2-binding adaptor protein TAPP1. 1451 76

The tumour suppressor PTEN is a PtdIns(3,4,5)P(3) phosphatase that regulates many cellular processes through direct antagonism of PI 3-kinase signalling. Here we show that oxidative stress activates PI 3-kinase-dependent signalling via the inactivation of PTEN. We use two assay systems to show that cellular PTEN phosphatase activity is inhibited by oxidative stress induced by 1 mM hydrogen peroxide. PTEN inactivation by oxidative stress also causes an increase in cellular PtdIns(3,4,5)P(3) levels and activation of the downstream PtdIns(3,4,5)P(3) target, PKB/Akt, that does not occur in cells lacking PTEN. We then show that endogenous oxidant production in RAW264.7 macrophages inactivates a fraction of the cellular PTEN, and that this is associated with an oxidant-dependent activation of downstream signalling. These results show that oxidants, including those produced by cells, can activate downstream signalling via the inactivation of PTEN. This demonstrates a novel mechanism of regulation of the activity of this important tumour suppressor and the signalling pathways it regulates. These results may have significant implications for the many cellular processes in which PtdIns(3,4,5)P(3) and oxidants are produced concurrently.
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PMID:Redox regulation of PI 3-kinase signalling via inactivation of PTEN. 1453 22

Cell numbers are regulated by a balance between processes of proliferation and apoptosis (programmed cell death). Proper regulation in a cell requires an accurate co-ordination between these two processes. Indeed, it has recently been found that dysregulation of cell cycle progression is essential for the initiation of apoptosis. Retinoblastoma protein (RB) is an important tumour suppressor and a cell cycle regulator. Most recent studies suggest that RB also plays a regulatory role in the process of apoptosis. During the onset of apoptosis, the hyperphosphorylated form of RB (p120/hyper) is converted to a hypophosphorylated form (p115/hypo), which is mediated by a specific protein-serine/ threonine phosphatase activity. The p115/hypo/RB may play an active role in the regulation of apoptosis. Accompanied by the endonucleosomal fragmentation of DNA, the newly formed p115/hypo/RB is immediately cleaved by a protease that has properties of the interleukin-1beta-converting enzyme family. By contrast, the unphosphorylated form of RB (p110/unphos) remains uncleaved during apoptosis. Further studies suggest that p110/unphos/RB functions as an inhibitor of apoptosis. Therefore, a balance between RB phosphatases and kinases and consequent RB phosphorylation status may be important for the determination of cellular fate.
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PMID:Putative roles of retinoblastoma protein in apoptosis. 1469 99

Targeting tumour suppressor gene pathways is an attractive therapeutic strategy in cancer. Since the first clinical trial took place in 1996, at least 20 other trials have investigated the possibility of restoring p53 function, either alone or in combination with chemotherapy, but with limited success. Other recent clinical trials have sought to harness abnormalities in the p53 pathway to permit tumour-selective replication of adenoviral vectors such as dl1520 (Onyx-015). Other tumour suppressor genes, such as retinoblastoma (Rb) and PTEN (phosphatase, tensin homologue, deleted on chromosome 10), are the targets for imminent clinical trials, while microarray technologies are revealing multiple new genes that are potential targets for future gene therapy.
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PMID:Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. 1476 96

The tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) plays essential roles in regulating signalling pathways involved in cell growth and apoptosis, and is inactivated in a wide variety of tumours. The role of PTEN as a tumour suppressor has been firmly established; however, the mechanism(s) by which its function and activity are regulated remains elusive. Here, we summarize recent progress in research directed towards trying to understand the molecular basis of regulatory mechanisms for PTEN. We also describe our novel finding that a tumour suppressor candidate protein binds to extreme C-terminal region of PTEN and regulates PTEN protein turnover.
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PMID:The tumour suppressor PTEN: involvement of a tumour suppressor candidate protein in PTEN turnover. 1504 5

Conventional approaches to identifying cancer targets are complicated by the chromosomal instability of tumour cells, and typically result in a large number of differentially expressed candidate genes with uncertain disease relevance. Here we present a novel approach which aims to elucidate the molecular changes that are induced after loss of tumour suppressor function. Using gene silencing tools, we mimic the loss of tumour suppressor function to identify key regulators of tumour initiation and progression. Loss of function of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) correlates with increased invasive cell growth due to the resulting chronic activation of the PI 3-kinase (phosphoinositide 3-kinase) pathway. Induced activation of PI 3-kinase either by inhibiting PTEN expression or by using p110*, a constitutively active PI 3-kinase, increased signalling and the invasive growth potential of cells. Using this unbiased approach we have identified novel downstream effectors of PI 3-kinase/PTEN signalling that mediate the behaviour of cells with a hyperactive PI 3-kinase pathway. These molecules represent candidate targets for therapeutic intervention in patients with PTEN-deficient tumours.
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PMID:Identification of novel effectors of invasive cell growth downstream of phosphoinositide 3-kinase. 1504 8

The tumour suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) shares homology with protein tyrosine phosphatases (PTPases). Similarly, bisperoxovanadium (bpV) molecules that are well-established PTPase inhibitors were shown to inhibit PTEN, but at up to 100-fold lower concentrations. The preference and potency of the bpVs towards PTEN was validated in vivo as demonstrated by: (i) an increase of Ser473 phosphorylation of protein kinase B (PKB) at similar low nanomolar doses, (ii) the lack of any effect on the PKB phosphorylation in the PTEN negative cell line UM-UC-3, (iii) the ability to rescue Ly294002-induced phosphoinositide 3-kinase inhibition and (iv) a lack of tyrosine phosphorylation at low nanomolar doses.
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PMID:Bisperoxovanadium compounds are potent PTEN inhibitors. 1514 64

The PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor is a PI (phosphoinositide) 3-phosphatase that can inhibit cellular proliferation, survival and growth by inactivating PI 3-kinase-dependent signalling. It also suppresses cellular motility through mechanisms that may be partially independent of phosphatase activity. PTEN is one of the most commonly lost tumour suppressors in human cancer, and its deregulation is also implicated in several other diseases. Here we discuss recent developments in our understanding of how the cellular activity of PTEN is regulated, and the closely related question of how this activity is lost in tumours. Cellular PTEN function appears to be regulated by controlling both the expression of the enzyme and also its activity through mechanisms including oxidation and phosphorylation-based control of non-substrate membrane binding. Therefore mutation of PTEN in tumours disrupts not only the catalytic function of PTEN, but also its regulatory aspects. However, although mutation of PTEN is uncommon in many human tumour types, loss of PTEN expression seems to be more frequent. It is currently unclear how these tumours lose PTEN expression in the absence of mutation, and while some data implicate other potential tumour suppressors and oncogenes in this process, this area seems likely to be a key focus of future research.
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PMID:PTEN function: how normal cells control it and tumour cells lose it. 1519 42

The PTEN tumour suppressor is a phosphatase that dephosphorylates phosphatidylinositol 3, 4, 5 triphosphate (PIP3) and protein substrates. PTEN function is modulated by its carboxy-terminal region, which contains several clustered phosphorylation sites and a PDZ-binding motif (PDZbm). Although PTEN growth suppression effect is well demonstrated, its additional biological roles are less well understood. DAF-18, a Caenorhabditis elegans homologue PTEN, is a component of the insulin/IGF-I signalling pathway that controls entry to the dauer larval stage and adult longevity. To further explore the role of PTEN in the insulin signalling cascade and its possible involvement in the mechanisms of ageing, we undertook a study of PTEN function in C. elegans. We now report that human PTEN can substitute for DAF-18 and restores the dauer and longevity phenotypes in worms devoid of DAF-18. Furthermore, we provide genetic and biochemical evidence that dauer and lifespan control depends on PTEN-mediated regulation of PIP3 levels. Finally, we established that phosphorylation sites in the C-terminus of PTEN and its PDZbm are necessary for PTEN control of the insulin/IGF-I pathway. These results demonstrate that PTEN negatively regulates the insulin/IGF pathway in a whole organism and raise the hypothesis that PTEN may be involved in mammalian ageing.
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PMID:The human tumour suppressor PTEN regulates longevity and dauer formation in Caenorhabditis elegans. 1563 88

The MSSE gene predisposes to multiple invasive but self-healing skin tumours (multiple self-healing epitheliomata). MSSE was previously mapped to chromosome 9q22-q31 and a shared haplotype in affected families suggested a founder mutation. We have refined the MSSE critical region (<1 cM, <1 Mb) between the zinc-finger gene ZNF169 and the Fanconi anaemia gene FANCC. By genetic mapping we have excluded ZNF169 and FANCC as well as PTCH (PATCHED) and TGFBR1 (transforming growth factor beta receptor type-1) genes. The CDC14B cell cycle phosphatase gene also lies in the region but screening of the complete coding region revealed no mutation in MSSE patients. Somatic cell hybrids created by haploid conversion of an MSSE patient's cells enabled screening of the MSSE chromosome 9 and showed no CDC14B deletion or mutation that abrogates CDC14B mRNA expression. Thus, CDC14B is unlikely to be the MSSE gene. We also report the first molecular analysis of MSSE tumours showing loss of heterozygosity of the MSSE region, with loss of the normal allele, providing the first evidence that MSSE is a tumour suppressor gene.
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PMID:The elusive multiple self-healing squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity. 1617 Mar 43


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