Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P43146 (tumour suppressor)
5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to identify the molecular mechanism of action of the isoflavone, genistein. Genistein at 0.15 mM caused MCF-7 apoptotic cell death, which was accompanied by cell cycle delay in the G2/M phase. Twenty-four hours post-treatment, 47.3% of the MCF-7 cells accumulated at G2/M, compared with 19.9% in the untreated controls. At 0.15 mM, genistein caused an increase in the steady-state levels of the wild-type tumour suppressor p53, which was attributed to stabilising the tumour suppressor protein, since p53 mRNA levels did not increase. Prior to the upregulation of p53, which became evident within 6 h of genistein treatment, there was increased bcl-2 phosphorylation at 30 min post-treatment. Although early changes (30-120 min) in the phosphotyrosine peptide patterns were not detected, after 24h, genistein inhibited phosphorylation of several peptides. These results suggest that genistein's dual roles of protein tyrosine kinase inhibitor and topoisomerase II inhibitor are essential for the initiation of apoptosis.
...
PMID:Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells. 1002 17

The tumour suppressor PTEN inhibits cell growth through multiple mechanisms. We have previously demonstrated that overexpression of PTEN in MCF-7 breast cancer cells causes G(1) arrest followed by cell death, the latter of which is believed to be mediated by the phosphoinositol-3-kinase (PI3K) and Akt/PKB pro-apoptotic pathways. In this present study, we show that culture in the presence of low levels of growth factors increased PTEN-mediated growth suppression through the enhancement of PTEN-induced cell death. The caspase 9-specific inhibitor, ZVAD, blocked PTEN-induced cell death without altering the effect of PTEN on cell cycle distribution. Depending on the level of expression, overexpression of dominant-negative Akt induces more cell death and has less effect on the cell cycle or induces similar or decreased cell death without affecting the cell cycle compared with effects on cell death and the cell cycle when overexpressing PTEN. These observations in sum suggest that, in MCF-7 breast cancer cells, the apoptotic cells induced by the overexpression of PTEN did not derive from the G(1)-arrested cells. Further, the effect of PTEN on cell death is mediated through the PI3K/Akt pathway whereas PTEN-mediated cell cycle arrests are through PI3K/Akt-dependent and -independent pathways.
...
PMID:PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways. 1115 42

The tumour suppressor gene PTEN/MMAC1/TEP1 has been implicated in a variety of human cancers and several inherited hamartoma tumour syndromes, including Cowden syndrome, which has a high risk of breast and thyroid cancer. We have previously reported that overexpression of PTEN in MCF-7 breast cancer cells induces cell cycle arrest and apoptosis. In this study, we analysed PTEN status at both the structural and expression levels and explored PTEN's growth-suppressive effects on thyroid. We found that 1 of 10 thyroid cancer lines [follicular thyroid carcinoma FTC-133] had hemizygous deletion and a splice variant IVS4--19G-->A in the remaining allele. Four lines, including FTC-133, express PTEN mRNA at low levels. In general, PTEN protein levels correlated with mRNA levels, except for NPA87, which has low levels of transcript and relatively high levels of PTEN protein. Transient expression of PTEN in seven thyroid cancer cell lines resulted in G(1) arrest in two well differentiated papillary thyroid cancer lines (PTCs) and both G(1) arrest and cell death in the remaining five lines, including three FTCs, one poorly differentiated PTC and one undifferentiated thyroid cancer. The level of phosphorylated Akt was inversely correlated with the endogenous level of PTEN protein and overexpression of PTEN-blocked Akt phosphorylation in all cells analysed. Our results suggest that downregulation of PTEN expression at the mRNA level plays a role in PTEN inactivation in thyroid cancer and PTEN exerts its tumour-suppressive effect on thyroid cancer through the inhibition of cell cycle progression alone or both cell cycle progression and cell death.
...
PMID:Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death. 1115 44

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.
...
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.
...
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

Breast cancer is the most common cancer in women worldwide and its incidence is increasing. Oestrogens and mitogenic growth factors may play an important role in the development of breast cancer, whereas inhibitory growth factors may prevent the development of breast cancer. Only about 5 to 10% of cases of breast cancer are due to inheritance of mutations in the BRCA1 or BRCA2 tumour suppressor genes. Mutations in the p53 tumour suppressor gene are commonly found in sporadic breast cancers. Retinoic acid and carotenoids may play a protective role in breast cancer since they inhibit the growth of the oestrogen receptor-positive MCF-7 breast cancer cell line. The presence of oestrogen and progesterone receptors predicts the likelihood of benefit from hormonal therapy. Amplification of the c-erbB2 oncogene in breast cancers is associated with a poor prognosis. It is now apparent that there is a complex, productive cross-talk between oestrogen-directed and growth factor-directed pathways which are believed to markedly reinforce their individual cellular effects on growth and gene responses.
...
PMID:Role of steroid hormones and growth factors in breast cancer. 1247 34

The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein and phosphatidylinositiol substrates and modulates cellular functions such as migration and proliferation. Germline mutations of PTEN have been shown to cause Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome. Recently, germline mutations in BMPR1A, the gene encoding the type 1A receptor of bone morphogenetic proteins (BMP) have been found in rare families with Cowden syndrome, suggesting that there may be a link between BMP signaling and PTEN. We thus sought to determine whether BMP2 stimulation alters PTEN protein levels in the breast cancer line, MCF-7. We found that exposure to BMP2 increased PTEN protein levels in a time- and dose-dependent manner. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, as cycloheximide treatment did not inhibit BMP2-induced PTEN accumulation, suggesting that BMP2 stimulation inhibited PTEN protein degradation. Indeed, we found that BMP2 treatment of MCF-7 cells decreased the association of PTEN with two proteins in the degradative pathway, UbCH7 and UbC9. These data indicate that BMP2 exposure can regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway. This opens up a new mode of regulating PTEN activity to be investigated further and may explain why BMPR1A can act as a minor susceptibility gene for PTEN mutation negative Cowden syndrome.
...
PMID:BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. 1262 Sep 73

Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20-45% of all hereditary cases. There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression. We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours. To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormone-insensitive) breast cancer cell lines using the MTT assay. The 50% inhibitory concentration (IC(50)) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure. HCC1937 cells were significantly (P<0.005) more sensitive to cisplatin (CDDP) (IC(50) : 30-40 microM) compared with MCF-7 (IC(50) : 60-70 microM) and MDA-MB231 (IC(50) : 90-100 microM) cells. On the other hand, BRCA1-defective breast cancer cells were significantly less sensitive to doxorubicin (Dox) (IC(50) : 45-50 microM) compared with MCF-7 (IC(50) : 1-5 microM) and MDA-MB231 (IC(50) : 5-10 microM) (P<0.02), as well as to paclitaxel (Tax) (IC(50) : >2 microM for HCC1937, 0.1-0.2 microM for MCF-7 and 0.01-0.02 microM for MDA-MB231) (P<0.001). Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/(WT)BRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar. BRCA1 reconstitution reverted the hypersensitivity to CDDP (P<0.02), and restored the sensitivity to Dox (P<0.05) and Tax (P<0.001), compared with parental HCC1937 cells. Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting.
...
PMID:BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. 1269 98

The tumour suppressor gene p53 and its protein controls critical cellular functions in cell cycle regulation as well as in apoptosis. Recently, in an in vitro study on breast cancer cell line MCF-7, the apoptotic function of p53 has been shown to be altered by overexpression of cyclin A. In this study we have demonstrated a similar association in a consecutive series of 166 breast cancer patients operated for invasive breast carcinomas. We detected mutations (exon 5-8) in the tumour tissue from 28 (16.0%) of the patients, and positive immunoreactivity of p53 protein was detected in tumour tissue samples from 32 (18.8%) patients. A statistically significant correlation between TP53 gene mutations and positive immunohistochemistry of p53 protein was observed (p = 0.0038). Mutations of the TP53 gene, as well as positive immunoreactivity to p53, were associated with poor prognosis (mutations p = 0.053, HR = 1.8, 95% CI 0.99-3.4; positive immunoreactivity p = 0.029, HR 1.33, 95% CI 1.0-1.7; mutation and/or positive immunoreactivity p = 0.015, HR 2.1, 95% CI 1.2-3.7) when cyclin A was not included in the survival analysis. However, when cyclin A overexpression was included, alteration of the p53 protein (mutations and/or positive immunoreactivity) lost its statistical power (p = 0.088). In a stratified survival analysis the OR fell from 3.0 (95% CI 1.2-8.3, p = 0.03) in the low-expression cyclin A stratum to 1.3 (95% CI 0.42-4.1, p = 0.77) in the overexpression cyclin A stratum.
...
PMID:Overexpression of cyclin A overrides the effect of p53 alterations in breast cancer patients with long follow-up time. 1290 23

The MCF-7 human breast carcinoma cell line is widely used as a model system by breast cancer researchers and cell biologists investigating apoptosis. Since its establishment 30 years ago, from a patient with metastatic breast cancer, the original MCF-7 cell population has undergone genetic drift to such an extent that numerous genetically diverse sublines now exist. For instance, it has been reported that MCF-7 cells have lost the region 3p21.3, to which the apoptosis regulatory protein and putative tumour suppressor LUCA-15 (also called RBM5 and H37) maps; however, LUCA-15 has been cloned from MCF-7 cells, and LUCA-15 expression analyses have been conducted using MCF-7 cells. To address this discrepancy, we characterized three MCF-7 sublines by Western blot, RT-PCR and finally genomic PCR analysis, and determined that one of the three had lost the LUCA-15 gene. Interestingly, loss of LUCA-15 was positively correlated with decreased susceptibility to the death-inducing ligand TNF-alpha. Subsequent overexpression of exogenous LUCA-15 was shown to enhance TNF-alpha-mediated apoptosis, suggesting that LUCA-15 may play a role in regulating the susceptibility of breast cancer cells to drug-induced apoptosis. These results not only reinforce the necessity of MCF-7 subline characterization, but provide the first evidence of an apoptotic modulatory role for LUCA-15 in a non-T cell line.
...
PMID:Genetic instability of RBM5/LUCA-15/H37 in MCF-7 breast carcinoma sublines may affect susceptibility to apoptosis. 1533 70


1 2 3 4 5 Next >>

---