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)

Smad4 is an essential signal transducer of the transforming growth factor beta (TGF-beta) signalling pathway and has been identified as a tumour suppressor, being mutated in approx. 50% of pancreatic cancers and approx. 15% of colorectal cancers. Two missense mutations in the C-terminal domain of Smad4, D351H (Asp351-->His) and D537Y (Asp537-->Tyr), have been described recently in the human colorectal cancer cell lines CACO-2 and SW948 respectively [Woodford-Richens, Rowan, Gorman, Halford, Bicknell, Wasan, Roylance, Bodmer and Tomlinson (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 9719-9723]. Previous work in vitro suggested that only Asp-351 was required for interaction with Smad2 [Wu, Fairman, Penry and Shi (2001) J. Biol. Chem. 276, 20688-20694]. In the present study, we investigate the functional consequences of these point mutations in vivo. We demonstrate that neither of these colorectal cancer cells undergo growth arrest in response to TGF-beta, which can be explained, at least in part, by their inability to up-regulate cyclin-dependent kinase inhibitors p21 (CIP1 ) or p15 ( INK4b) after TGF-beta stimulation. Although the point-mutated Smad4s are expressed at normal levels in these colorectal cancer cells, they cannot interact with either TGF-beta-induced phosphorylated Smad2 or Smad3. As a result, these Smad4 mutants do not accumulate in the nucleus after TGF-beta stimulation, are not recruited to DNA by relevant Smad-binding transcription factors and cannot generate transcriptionally active DNA-bound complexes. Therefore both these colorectal tumour cells completely lack functional Smad4 activity owing to the missense mutations. Given the location of these mutations in the three-dimensional structure of the Smad4 C-terminal domain, the results also give us significant insights into Smad complex formation.
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PMID:Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells. 1471 79

We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases. Activities of endogenous NUAK2, QIK, QSK, SIK, MARK1, MARK2/3 and MARK4 were markedly reduced in LKB1-deficient cells. Neither LKB1 activity nor that of AMPK-related kinases was stimulated by phenformin or AICAR, which activate AMPK. Our results show that LKB1 functions as a master upstream protein kinase, regulating AMPK-related kinases as well as AMPK. Between them, these kinases may mediate the physiological effects of LKB1, including its tumour suppressor function.
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PMID:LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. 1497 52

Intracellular levels of phosphorylation are regulated by the coordinated action of protein kinases and phosphatases. Disregulation of this balance can lead to cellular transformation. Here we review knowledge of the mechanisms of one protein phosphatase, the tumour suppressor PTEN/MMAC/TEP 1 apropos its role in tumorigenesis and signal transduction. PTEN plays an important role in the phosphatidyl-inositol-3-kinase (PI3-K) pathway by catalyzing degradation of phosphatidylinositol-(3,4,5)-triphosphate generated by PI3-K. This inhibits downstream targets mainly protein kinase B (PKB/Akt), cell survival and proliferation. PTEN contributes to cell cycle regulation by blockade of cells entering the S phase of the cell cycle, and by upregulation of p27(Kip1) which is recruited into the cyclin E/cdk2 complex. PTEN also modulates cell migration and motility by regulation of the extracellular signal-related kinase - mitogen activated protein kinase (ERK-MAPK) pathway and by dephosphorylation of focal adhesion kinase (FAK). We also emphasize the increasingly important role that PTEN has from an evolutionary point of view. A number of PTEN functions have been elucidated but more information is needed for utilization in clinical application and potential cancer therapy.
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PMID:The mechanism of action of the tumour suppressor gene PTEN. 1503 1

Studies of the HEDGEHOG signalling pathway in Drosophila have revealed a functional link between two genes, cubitus interruptus and patched, whose human homologues are, respectively, a proto-oncogene and a tumour suppressor. While the former has been implicated as a transcription factor, controversy has surrounded the function of the transmembrane protein encoded by the latter. Somewhere in the signal-transduction pathway between these two lies protein kinase A (PKA), and now SMOOTHENED, whose similarity to G-protein-coupled receptors suggests a link with PKA, has also been implicated in the pathway. This article summarizes the current understanding of the pathway and the interactions between these proteins.
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PMID:'Smoothening' the path for hedgehogs. 1515

Premalignant conditions affect the larynx. Dysplasia can progress in severity resulting in cancer depending on many clinical, pathological and molecular factors. The purpose of this study was to examine the expression of the p21 and p27 cyclin-dependent kinase inhibitors and p53 tumour suppressor gene in dysplasia of the larynx. A total of 114 cases of untreated dysplasia were selected from the archives of the University of Newcastle. p21, p27 and p53 immunohistochemistry was performed and the cases followed up. Twenty-eight dysplasias (24%) subsequently developed into cancers. Expression of the molecular factors studied was not associated with cancer progression. p53 expression was associated with smoking (P = 0.005). In contrast, grade of dysplasia was significantly associated with cancer risk (odds ratio 6.7; P = 0.0001). The majority (75%) of cancers were detected within 12 months of dysplasia being diagnosed.
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PMID:Molecular markers in dysplasia of the larynx: expression of cyclin-dependent kinase inhibitors p21, p27 and p53 tumour suppressor gene in predicting cancer risk. 1553 63

The neurofibromatosis 2 tumour suppressor merlin/schwannomin is structurally related to the ezrin-radixin-moesin family of proteins, which anchor actin cytoskeleton to specific membrane proteins and participate in cell signalling. Merlin inhibits cell growth with a yet unknown mechanism. As most tumour suppressors are linked to cell cycle control, we investigated merlin's behaviour during cell cycle. In glioma and osteosarcoma cells, endogenous merlin was targeted to the nucleus in a cell cycle-specific manner. Merlin accumulated perinuclearly at the G2/M phase, and shifted to the nucleus at early G1. During mitosis, merlin localized to mitotic spindles and at the contractile ring. Nuclear merlin was strongly reduced in confluent cells. Blocking of the CRM1/exportin nuclear export pathway led to accumulation of merlin in the nucleus. Activation of the p21-activated kinase or protein kinase A, which result in phosphorylation of merlin, did not affect its nuclear localization. Merlin regulates the activity of extracellular signal-regulated kinase 2 (ERK2) and nuclear localization of both proteins was induced by cell adhesion. Unlike ERK2, nuclear localization of merlin was not, however, dependent on intact actin cytoskeleton. These results link merlin to events related to cell cycle control and may help to resolve its tumour suppressor function.
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PMID:Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin. 1558 Feb 88

Recent work has shown that the LKB1 tumour suppressor protein kinase phosphorylates and activates protein kinases belonging to the AMP activated kinase (AMPK) subfamily. In this study, we identify the sucrose non-fermenting protein (SNF1)-related kinase (SNRK), a largely unstudied AMPK subfamily member, as a novel substrate for LKB1. We demonstrate that LKB1 activates SNRK by phosphorylating the T-loop residue (Thr173), and that the LKB1 regulatory subunits STRAD and MO25 are required for LKB1 to activate SNRK. We find that SNRK is not active when expressed in HeLa cells that lack expression of LKB1, and its activity is restored by expression of wild type LKB1, but not catalytically deficient LKB1. We also present evidence that two other AMPK-related kinases more distantly related to AMPK than SNRK, namely NIM1 and testis-specific serine/threonine kinase-1 (TSSK1) are not substrates for LKB1. Tissue distribution analysis indicates that SNRK protein is mainly expressed in testis, similar to TSSK isoforms, whereas NIM1 is more widely expressed. These results provide evidence that SNRK could mediate some of the physiological effects of LKB1.
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PMID:Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate. 1573 51

The anti-proliferative effect of the ErbB2 specific antibody Herceptin in cells overexpressing ErbB2 has previously been explained by endocytic downregulation of ErbB2. However, in the following, we demonstrate that Herceptin inhibited proliferation of ErbB2 overexpressing cells without downregulating ErbB2. Herceptin did also not induce endocytosis of ErbB2. Herceptin was found to blunt proliferation of SKBr3 cells overexpressing EGFR, ErbB2, and ErbB3 and expressing functional PTEN, probably by recruiting PTEN to the plasma membrane. Akt was found to be constitutively phosphorylated both in SKBr3 cells overexpressing EGFR, ErbB2 and ErbB3, and in SKOv3 cells, overexpressing EGFR and ErbB2. However, phosphorylation of Akt was inhibited by Herceptin only in SKBr3 cells. SKOv3 cells, which lack the tumour suppressor protein Ras homolog member I, was found to have constitutively phosphorylated mitogen activated protein kinase and functionally increased Ras activity. SKOv3 cells further had low expression levels of PTEN. We thus confirm that the anti-proliferative effect of Herceptin in SKBr3 cells is due to recruitment of PTEN to the plasma membrane and conclude that Herceptin does not blunt phosphatidyl inositol 3 kinase-induced growth in cells with constitutive Ras activity. We further conclude that endocytic downregulation of ErbB2 does not contribute to Herceptin's antiproliferative effect.
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PMID:Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. 1580 Sep 44

Recent studies indicate that the LKB1 tumour suppressor protein kinase is the major "upstream" activator of the energy sensor AMP-activated protein kinase (AMPK). We have used mice in which LKB1 is expressed at only approximately 10% of the normal levels in muscle and most other tissues, or that lack LKB1 entirely in skeletal muscle. Muscle expressing only 10% of the normal level of LKB1 had significantly reduced phosphorylation and activation of AMPKalpha2. In LKB1-lacking muscle, the basal activity of the AMPKalpha2 isoform was greatly reduced and was not increased by the AMP-mimetic agent, 5-aminoimidazole-4-carboxamide riboside (AICAR), by the antidiabetic drug phenformin, or by muscle contraction. Moreover, phosphorylation of acetyl CoA carboxylase-2, a downstream target of AMPK, was profoundly reduced. Glucose uptake stimulated by AICAR or muscle contraction, but not by insulin, was inhibited in the absence of LKB1. Contraction increased the AMP:ATP ratio to a greater extent in LKB1-deficient muscles than in LKB1-expressing muscles. These studies establish the importance of LKB1 in regulating AMPK activity and cellular energy levels in response to contraction and phenformin.
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PMID:Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. 1588 49

Renal cell carcinomas (RCCs) of the clear cell type are associated with alteration of the von Hippel-Lindau (VHL) tumour suppressor gene as well as subsequent stabilization and over-expression of hypoxia inducible factor (HIF), which causes up-regulation of cyclin D1. On the basis of their ability to interact with cyclin D1 we investigated a number of cell cycle proteins to shed further light on the downstream effects of HIF dysregulation. Expression of HIF1alpha, cyclin D1, cyclin-dependent kinase 4 and cyclin-dependent kinase inhibitors p16, p21 and p27 was studied by immunohistochemistry. Since NFkappaB1/RelA have been shown to bind to the cyclin D1 promoter, mRNA expression of these transcription factors was further analysed by quantitative PCR. In RCCs harbouring VHL mutations/hypermethylation, over-expression of HIF1alpha was parallelled by up-regulation of cyclin D1 and CDK4 and down-regulation of p21 and p27. Moreover, p27 expression was inversely correlated with tumour cell differentiation. Comparison of non-tumorous autologous kidney tissues revealed a significant down-regulation of NFkappaB1 mRNA expression in patients harbouring RCC with VHL mutations/hypermethylation. Our data support the notion of a link between VHL deficiency/HIF dysfunction and disturbances of cell cycle control in the tumorigenesis of VHL-negative RCC.
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PMID:Concomitant deregulation of HIF1alpha and cell cycle proteins in VHL-mutated renal cell carcinomas. 1599 Oct 6


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