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)

The adenomatous polyposis coli gene is mutated in familial adenomatous polyposis and in sporadic colorectal tumours. The adenomatous polyposis coli gene product is a 300,000 mol. wt cytoplasmic protein that binds to at least three other proteins; beta-catenin, a cytoplasmic E-cadherin-associated protein; hDLG, a human homologue of the Drosophila discs large tumour suppressor protein and glycogen synthase kinase 3 beta, a mammalian homologue of the Drosophila ZESTE WHITE 3 protein. The adenomatous polyposis coli gene is highly expressed in the brain, suggesting that it may be involved in nerve function. Here we show that adenomatous polyposis coli is localized in the pericapillary astrocytic endfeet throughout the mouse central nervous system. Adenomatous polyposis coli is also localized in the astrocytic processes in the cerebellar granular layer, and displays concentrated expression in the terminal plexuses of the basket cell fibres around Purkinje cells. Adenomatous polyposis coli is further expressed in neuronal cell bodies and/or nerve fibres in the olfactory bulb, hippocampus, brain stem, spinal cord and dorsal root ganglia. Adenomatous polyposis coli is demonstrated to be co-localized with beta-catenin and/or hDLG in neurons and nerve fibres, but not in astrocytes. From these results, adenomatous polyposis coli is suggested to participate in a signal transduction pathway in astrocytes which is independent of beta-catenin and hDLG, and also in regulation of neuronal functions in association with beta-catenin and hDLG.
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PMID:Localization of the adenomatous polyposis coli tumour suppressor protein in the mouse central nervous system. 948 69

Maspin is a member of the serpin family of protease inhibitors. It is a 42 kDa cytoplasmic protein that is reported to have tumour suppressor activity. The loss of maspin gene expression is correlated with increased invasiveness and the risk of metastases in breast cancer. We studied maspin expression in primary melanoma lesions obtained from 76 patients. Immunostaining of 5 pm sections for maspin expression was obtained using the citrate antigen retrieval method. The extent of immunostaining was scored by recording the proportion of immunoreactive cells and the intensity of immunostaining. Our results demonstrated that maspin expression was down-regulated in intermediate thickness and thick melanoma lesions compared with thin lesions. These results suggest that loss of maspin expression might play a role in melanoma progression, invasion and metastatic dissemination. Further studies are needed to clarify the clinicopathological significance of maspin expression in melanoma.
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PMID:Decreased immunoreactive maspin expression in intermediate thickness and thick primary melanoma lesions. 1660 23

Beclin 1 is is an autophagy gene, the role of which as a tumour suppressor has recently been recognized in a few studies. We examined the expression of Beclin 1 protein in 212 primary human brain tumours, including 97 high-grade glial tumours, 29 low-grade glial tumours, 4 grade III meningiomas, 19 grade II meningiomas, 52 grade I meningiomas, and 11 medulloblastomas. In 94 cases, including 56 glial tumours, 35 meningiomas, and 3 medulloblastomas we also assessed Beclin 1 mRNA expression by real-time RT-PCR. In most high-grade astrocytic, ependymal neoplasms and atypical meningiomas we found a decrease of cytoplasmic protein expression that was, instead, high in the majority of low-grade tumours and in medulloblastomas. The expression level of Beclin 1 mRNA was significantly lower in glioblastomas than in grade II (p=0.04) and grade I (p=0.01) astrocytomas; in grade III than in grade I astrocytomas (p=0.01); in grade II than in grade I meningiomas (p=0.03); and in all glial tumours when compared to all meningiomas (p<0.0001). Cytoplasmic expression is thought to be linked to the functional protein. Our observations are in line with studies that demonstrated decreased expression of Beclin 1 in human breast, ovarian, prostate and ovarian cancer and furtherly support its involvement also in brain tumours, which had previously been demonstrated in a few experimental studies, both in spontaneous and in therapy-induced autophagy. Furthermore, our study suggests possible differences of Beclin 1 involvement and its role among the different histotypes of brain neoplasms. Further studies are needed to highlight Beclin 1 function in tumour suppression and/or in tumour survival through autophagy and other related programmed cell death processes in brain tumours.
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PMID:Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours. 1720 25

The von Hippel-Lindau tumour suppressor protein (pVHL) participates in many cellular processes including oxygen sensing, microtubule stability and primary cilia regulation. Recently, we identified ATP-dependent motor complex kinesin-2 to endogenously bind the full-length variant of VHL (pVHL30) in primary kidney cells, and mediate its association to microtubules. Here we show that pVHL also endogenously binds the neuronal kinesin-2 complex, which slightly differs from renal kinesin-2. To investigate the role of kinesin-2 in pVHL mobility, we performed fluorescence recovery after photobleaching (FRAP) experiments in neuroblastoma cells. We observe that pVHL30 is a highly mobile cytoplasmic protein, which becomes an immobile centrosomal protein after ATP-depletion in living cells. This response to ATP-depletion is independent of GSK3beta-dependent phosphorylation of pVHL30. Furthermore, VHL variant alleles with reduced binding to kinesin-2 fail to respond to ATP-depletion. Accordingly, interfering with pVHL30-KIF3A interaction by either overexpressing a dominant negative construct or by reducing endogenous cellular levels of KIF3A by RNAi abolishes pVHL's response to ATP-depletion. From these data we suggest that mobility of a subcellular pool of pVHL is regulated by the ATP-dependent kinesin-2 motor. Kinesin-2 driven mobility of cytoplasmic pVHL might enable pVHL to function as a tumour suppressor.
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PMID:Mobility of the von Hippel-Lindau tumour suppressor protein is regulated by kinesin-2. 1826 24

TSC2 (Tuberous sclerosis complex 2) is an important tumour suppressor gene, mutations within which are linked to the development of tuberous sclerosis and implicated in multiple tumour types. TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth. Here, we report the characterisation of a novel isoform of TSC2 which is under direct control of the ligand-activated androgen receptor. TSC2 isoform A (TSC2A) is derived from an internal androgen-regulated alternative promoter and encodes a 508-amino acid cytoplasmic protein corresponding to the C-terminal region of full-length TSC2, lacking the interaction domain for TSC1 and containing an incomplete interaction domain required for Rheb inactivation. Expression of TSC2A is induced in response to androgens and full-length TSC2 is co-ordinately down-regulated, indicating an androgen-driven switch in TSC2 protein isoforms. In contrast to the well-characterised suppressive effect on cell proliferation of full-length TSC2 protein, both LNCaP and HEK293 cells over-expressing TSC2 isoform A proliferate more rapidly (measured by MTT assays) and have increased levels of cells in S-phase (measured by both Edu staining and FACS analysis). Our work indicates, for the first time, a novel role for this well-known tumour suppressor gene, which encodes an activator of cell proliferation in response to androgen stimulation.
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PMID:A novel androgen-regulated isoform of the TSC2 tumour suppressor gene increases cell proliferation. 2431 44

Transfer RNAs (tRNAs) are essential for mRNA translation. They are transcribed in the nucleus by RNA polymerase III and undergo many modifications before contributing to cytoplasmic protein synthesis. In this review I highlight our understanding of how tRNA biology may be linked to the regulation of mRNA translation, growth and tumorigenesis. First, I review how oncogenes and tumour suppressor signalling pathways, such as the PI3 kinase/TORC1, Ras/ERK, Myc, p53 and Rb pathways, regulate Pol III and tRNA synthesis. In several cases, this regulation contributes to cell, tissue and body growth, and has implications for our understanding of tumorigenesis. Second, I highlight some recent work, particularly in model organisms such as yeast and Drosophila, that shows how alterations in tRNA synthesis may be not only necessary, but also sufficient to drive changes in mRNA translation and growth. These effects may arise due to both absolute increases in total tRNA levels, but also changes in the relative levels of tRNAs in the overall pool. Finally, I review some recent studies that have revealed how tRNA modifications (amino acid acylation, base modifications, subcellular shuttling, and cleavage) can be regulated by growth and stress cues to selectively influence mRNA translation. Together these studies emphasize the importance of the regulation of tRNA synthesis and modification as critical control points in protein synthesis and growth. This article is part of a Special Issue entitled: Translation and Cancer.
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PMID:Why should cancer biologists care about tRNAs? tRNA synthesis, mRNA translation and the control of growth. 2549 80