Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence supports a role for EphB receptor tyrosine kinases as tumour suppressors in colorectal and prostate cancer. However, it is unclear how these receptors inhibit cancer cell tumorigenicity - an activity that is highly unusual for a family of receptor tyrosine kinases. Here, we report that the EphB4 receptor can behave as a tumour suppressor in a mouse xenograft model of breast cancer when stimulated by its ligand, ephrin-B2. In breast cancer cells, EphB4 activates an antioncogenic pathway involving Abl family tyrosine kinases and the Crk adaptor protein. This Abl-Crk pathway inhibits breast cancer cell viability and proliferation in addition to motility and invasion, and also downregulates the pro-invasive matrix metalloprotease, MMP-2. Consistent with these effects, EphB4 and the Abl-Crk pathway are constitutively active in non-transformed mammary epithelial cells. These findings identify a novel Eph receptor signalling pathway with tumour-suppressor activity and predict that therapeutic intervention to activate EphB4 signalling will inhibit tumour progression.
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PMID:The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. 1688 Aug 9

Com-1, candidate of metastasis-1, also known as p8, is a recently discovered molecule with a putative role in determining the metastatic nature of cancer cells. We have investigated the expression of Com-1 in normal and malignant human prostate tissues and its molecular interaction within prostate cancer cells. The expression of Com-1 in human prostate tissues and prostate cancer cell lines was assessed at both the mRNA and protein levels, by RT-PCR and immunohistochemistry. The staining intensity of Com-1 was semiquantified using computer assisted image analysis. Full- length Com-1 cDNA was isolated from normal mammary tissues. Ribozyme transgenes that specifically target human Com-1 were constructed using the pEF6/V5-His vector. The growth of prostate cancer cells in vitro and tumour growth in vivo (athymic mice model) following Com-1 overexpression in prostate cancer cells were determined. In normal prostate tissues, the epithelial cells strongly stained Com-1, both in the cytoplasm and in the nucleus. In contrast, prostate cancer cells in tumour tissue showed substantially reduced Com-1 staining levels (p < 0.05 compared to normal cells for both cytoplasmic and nucleus staining), whereas the prostate cancer cell lines PC-3, DU145 and CA-HPV10 widely expressed Com-1. Transfection of these cells with hammerhead ribozyme transgenes resulted in the loss of expression of the Com-1 transcript. Using an in vitro invasion assay we found that the loss of Com-1 from prostate cancer cells increased their invasiveness. Knockout of Com-1 also resulted in the accelerated growth of all three cell lines. Forced overexpression of Com-1/ p8 in prostate cancer cells was able to reverse the changes in invasiveness and growth seen with the Com-1 knock-out cells. In a spontaneous tumour model, it was demonstrated that PC-3 cells with forced overexpression of Com-1 (PC-3com1Exp) had a significantly slower rate of growth compared with control cells (tumour size 36.6 +/- 31.2 vs 114.3 +/- 68.1 mm3, for tumours from PC-3com1Exp and control PC-3 cells, respectively, p = 0.0023). In conclusion, Com-1/p8 was expressed at lower levels in human prostate cancer cells compared with normal epithelial cells. Com-1/p8 levels are inversely correlated with the invasiveness and growth of prostate cancer cells in vitro and the overexpression of Com-1 reduced the growth of prostate tumours in vivo. Com-1/p8 is a potential tumour suppressor in human prostate cancer.
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PMID:Com-1/p8 acts as a putative tumour suppressor in prostate cancer. 1701 31

Com-1, candidate of metastasis-1, also known as p8, has been shown to regulate the growth and apoptosis of cancer cells and is associated with the disease progression in human cancers including prostate cancer. In the current study, we investigated a potential mechanism underlying the anticancer action of Com-1/p8 in human prostate cancer. Human prostate cancer cells were used. Full-length Com-1 cDNA was isolated from normal mammary tissues. Ribozyme transgenes that specifically target human Com-1 were constructed using the pEF6/V5-His vector. Com-1 interacting proteins were determined using immunoprecipitation method. Cell growth and invasiveness were investigated using in vitro methods. Using immunoprecipitation and Western blotting, Com-1 was found to be cross-reprecipitated with PGC-1, a coactivator of peroxisome proliferator activated receptor (PPAR)-gamma, but not PPAR-gamma itself. Elimination of Com-1 from prostate cancer cells resulted in a reduced response of the cells to ciglitizone, a PPAR-gamma agonist, whereas forced expression of Com-1 rendered cells more responsive to ciglitizone. We further demonstrated that the overexpression of Com-1/p8 resulted in changes in the expression of the PGC-1 responsive gene, fatty acid synthase (FAS). Com-1 may act as a tumour suppressor in human prostate cancer cells. The potential tumour suppressive effect of Com-1 is at least partly via its interaction with PGC-1, the PPAR-gamma coactivator.
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PMID:Does the PGC-1/PPARgamma pathway play a role in Com-1/p8 mediated cell growth inhibition in prostate cancer? 1708 23

Deregulation of protease expression and activity is known to play an important role in tumour progression of malignant melanoma. The serpin maspin, a tumour suppressor in breast and prostate cancer was described as an inhibitor of cell migration and inducer of cell adhesion between the basement membrane and extracellular matrix resulting in inhibition of tumour metastasis. In contrast, overexpression of maspin is correlated with poor prognosis in other cancers. However, little is known about expression, regulation and function of maspin in malignant melanoma. In this study, we found loss of maspin expression in malignant melanoma cells compared with normal human epidermal melanocytes, which was analysed by quantitative real-time PCR, Western blot analysis, immunohistochemistry and microarray. For functional studies, melanoma cell clones stably transfected with a maspin expression vector were tested for changes in proliferation, migration and invasion. Although we could not see differences in proliferation and migration, we detected strongly reduced invasive capacity in the melanoma cell clones in which maspin is re-expressed compared with control. Reduced invasive potential was also detected in three different melanoma cell lines transiently transfected with a maspin expression vector. Furthermore, exogenously added maspin alone was sufficient to reduce invasion in MelIm significantly, indicating that maspin directly inhibits invasion on the cell surface. In summary, we believe that maspin is a tumour suppressor in malignant melanoma.
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PMID:Loss of maspin expression contributes to a more invasive potential in malignant melanoma. 1737 37

Par-4 (prostate apoptosis response 4) is a pro-apoptotic protein and tumour suppressor that was originally identified as a gene product up-regulated during apoptosis in prostate cancer cells. Here, we show, for the first time, that Par-4 is expressed and co-localizes with the actin filament bundles in vascular smooth muscle. Furthermore, we demonstrate that targeting of ZIPK to the actin filaments, as observed upon PGF-2alpha stimulation, is inhibited by the presence of a cell permeant Par-4 decoy peptide. The same decoy peptide also significantly inhibits PGF-2alpha induced contractions of smooth muscle tissue. Moreover, knockdown of Par-4 using antisense morpholino nucleotides results in significantly reduced contractility, and myosin light chain and myosin phosphatase target subunit phosphorylation. These results indicate that Par-4 facilitates contraction by targeting ZIPK to the vicinity of its substrates, myosin light chain and MYPT, which are located on the actin filaments. These results identify Par-4 as a novel regulator of myosin light chain phosphorylation in differentiated, contractile vascular smooth muscle.
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PMID:The pro-apoptotic protein Par-4 facilitates vascular contractility by cytoskeletal targeting of ZIPK. 1850 70

Prostate cancer (CaP) is the most frequently diagnosed malignant tumour and the second leading cause of cancer deaths in American men. One of the most troubling aspects of this disease is that, after androgen ablation therapy, androgen-dependent cancer cells inevitably progress to an androgen-independent status, for which no effective treatment has yet been developed. To date, the mechanisms that underlie the occurrence and progression of CaP remain largely unknown. Recent studies suggest that microRNAs (miRNAs) are involved in human tumourigenesis. Some aberrantly expressed miRNAs have been discovered in CaP cell lines, xenografts and clinical tissues and these CaP-related miRNAs may play critical roles in the pathogenesis of CaP. This review provides an overview of current findings about aberrantly expressed miRNAs in CaP. Although a number of CaP-related miRNAs were discovered, to date, only five are characterized for their functionalities: three as oncogenes and two as tumour suppressors. To understand the mechanisms of miRNA action as oncogenes or tumour suppressors, mRNA targets of miRNAs were characterized. Oncogenic miRNAs down-regulate the expression of apoptosis-related genes, and tumour suppressor miRNAs target the proliferation-related genes. Importantly, there is evidence that CaP-related miRNAs are regulated through androgen signalling and that this regulation may contribute to the development of androgen independence. Due to the oncogenic or tumour-suppressive properties of CaP-related miRNAs, they are highly likely to be of clinical use first as biomarkers but more importantly as therapeutic targets for prostate cancer treatment in the near future.
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PMID:MicroRNAs and prostate cancer. 1862 68

Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML-RARalpha fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARalpha degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.
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PMID:The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. 1871 20

Regucalcin plays an important role in maintenance of intracellular Ca(2+) homeostasis, suppresses cell proliferation, inhibits expression of oncogenes, and increases the expression of tumour suppressor genes. This suggests that regucalcin functions may be altered in cancer tissues. In this study the regucalcin expression in breast and prostate cancer cases was analysed by RT-PCR and immunohistochemistry showing that the mRNA and/or protein are under-expressed in these tumors. The effect of sex steroid hormones on regucalcin expression in breast and prostate cancer cells was determined by real-time PCR. MCF-7 and LNCaP cells were stimulated with 0, 1, and 10 nM of 17beta-estradiol (E(2)) or 5alpha-dihydrotestosterone (DHT), respectively, for 0, 6, 12, 24, and 48 h. MCF-7 cells were also stimulated with E(2) conjugated to BSA (E(2)-BSA). To explore the mechanisms underlying the sex steroid regulation of regucalcin expression, control treatments with ICI 182,780, flutamide and cyclohexamide were carried out. E(2) effects regulating regucalcin expression were not abrogated in the presence of ICI 182,780, and were similar to those observed with E(2)-BSA, which suggests the involvement of a membrane-bound estrogen receptor. In LNCaP cells, DHT down-regulated regucalcin expression, an effect inhibited by the presence of both flutamide and cyclohexamide, suggesting the involvement of androgen receptor and de novo protein synthesis. The loss of regucalcin expression in breast and prostate cancer cases and the regulation of its expression by sex steroid hormones suggest that it may be associated with development and progression of these human tumors.
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PMID:Regucalcin is under-expressed in human breast and prostate cancers: Effect of sex steroid hormones. 1934 72

Recent studies using genetically modified mice, such as FGF23-/- and Klotho-/- mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1alpha-hydroxylase activity seems to be a cause of the premature aging. In several studies, we have described that a complete or partial lack of vitamin D action (VDR-/- mice and CYP27B1-/-) show almost similar phenotype as FGF23-/- or Klotho-/- mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1-/- mice do not show alopecia nor balance deficit, which might be apoVDR-dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena. Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin-megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging-related chronic diseases more directly than calcitriol. Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-kappaB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer. Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40-60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging-associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given.
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PMID:Vitamin D and aging. 1944 37

In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3-1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells that express Nkx3-1 in the absence of testicular androgens (castration-resistant Nkx3-1-expressing cells, CARNs) are bipotential and can self-renew in vivo, and single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3-1 mutant mice in serial prostate regeneration suggest that Nkx3-1 is required for stem cell maintenance. Furthermore, targeted deletion of the Pten tumour suppressor gene in CARNs results in rapid carcinoma formation after androgen-mediated regeneration. These observations indicate that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.
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PMID:A luminal epithelial stem cell that is a cell of origin for prostate cancer. 1974 7


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