Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Se-allylselenocysteine (ASC) is effective in inhibiting mammary epithelial cell growth in vitro and mammary carcinogenesis in vivo, but its mechanism is unknown. We recently reported that ASC reduces cell growth in a dose- and time-dependent manner, induces a loss of DNA integrity, and increases apoptosis. However, the level of ASC required for growth inhibition in vitro is 10- to 20-fold higher than that required in vivo. One possible explanation for this difference is that the cells used in in vitro studies have limited lyase activity required to release the allyl Se moiety from selenocysteine, whereas animals have abundant lyase activity in tissues. In the present study, we found that methionine gamma-lyase (MGL) added to culture medium containing ASC produced biological effects with lower levels of ASC, comparable to the selenium levels in plasma achieved during in vivo chemoprevention. The combination of 2.5 microM ASC and MGL inhibited the growth of TM12 cells and increased apoptosis without loss of DNA integrity. Treatment of TM12 cells with ASC and MGL resulted in an elevation of the protein levels of p53, Cip1/p21, and Kip1/p27, concomitant with a decrease in cyclins D1 and E and modest reductions in cyclin-dependent kinase inhibitors 4 and 2. Cells treated with ASC and MGL also showed decreased phosphorylation of retinoblastoma tumor-suppressor protein. Taken together, these results suggest that a physiologically relevant concentration of ASC with MGL exerts an inhibitory effect on cell growth and that this effect is likely to involve modulation of signaling pathways that suppress the phosphorylation of retinoblastoma tumor-suppressor protein.
Mol Carcinog 2000 Dec
PMID:Activity of Se-allylselenocysteine in the presence of methionine gamma-lyase on cell growth, DNA integrity, apoptosis, and cell-cycle regulatory molecules. 1117 Feb 56

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.
Hum Mol Genet 2001 Mar 15
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

Zearalenone is a naturally occurring estrogenic contaminant of moldy feeds and is present in high concentrations in dairy products and cereals. Zearalenone was postulated to contribute to the overall estrogen load of women, but the mechanisms of its action are not known. We demonstrated that zearalenone could stimulate the growth of estrogen receptor-positive human breast carcinoma cell line MCF-7. In addition, zearalenone functioned as an antiapoptotic agent by increasing the survival of MCF-7 cell cultures undergoing apoptosis caused by serum withdrawal. Treatment of these cells with 100 nM zearalenone induced cell-cycle transit after increases in the expression of c-myc mRNA and cyclins D1, A, and B1 and downregulation of p27(Kip-1). G(1)/G(2)-phase kinase activity and phosphorylation of the retinoblastoma gene product was also evident. Flow cytometric analysis demonstrated entry of cells into the S and G(2)/M phases of the cell cycle, and phosphorylation of histone H3 occurred 36 h after zearalenone treatment. Ectopic expression of a dominant-negative p21(ras) completely abolished the zearalenone-induced DNA synthesis in these cells, and the specific inhibitor PD98059 for mitogen/extracellular-regulated protein kinase kinase arrested S-phase entry induced by zearalenone. These data suggest that the mitogen-activated protein kinase signaling cascade is required for zearalenone's effects on cell-cycle progression in MCF-7 cells. Given the presence of this mycotoxin in cereals, milk, and meat, the possibility that zearalenone is a potential promoter of breast cancer tumorigenesis should be investigated further. Mol. Carcinog. 30:88-98, 2001.
Mol Carcinog 2001 Feb
PMID:Signal transduction through the Ras/Erk pathway is essential for the mycoestrogen zearalenone-induced cell-cycle progression in MCF-7 cells. 1124 56

The sensitive-to-apoptosis gene (SAG) was initially identified as a redox-inducible, apoptosis-protective protein and subsequently found to be the second family member of regulator of cullins (ROC)/RING box protein (Rbx)/Hrt, which acts as a component of E3 ubiquitin ligase. We report here that SAG promoted cell growth under serum starvation. Microinjection of SAG mRNA into quiescent NIH/3T3 cells induced S-phase entry as determined by [(3)H]-thymidine incorporation. Likewise, overexpression of SAG by either adenovirus infection of immortalized human epidermal keratinocytes (Rhek-1) or DNA transfection of SY5Y human neuroblastoma cells induced cell proliferation under serum starvation. Because cyclin-dependent kinase inhibitors (CKIs), including p21, p27, and p57, are degraded through the ubiquitin pathway, we tested whether SAG-induced cell growth is associated with CKI degradation. Although there was no significant difference in the levels of p21 and p57 between the vector controls and SAG-overexpressing cells, serum starvation induced 10- to 18-fold accumulation of p27 in control Rhek-1 cells. Accumulation of p27 was remarkably inhibited (only 2 to 5-fold) in SAG-infected cells. Inhibition of p27 accumulation was also observed in stably SAG-overexpressing SY5Y cells. Significantly, SAG-associated inhibition of p27 accumulation was largely abolished by the treatment with a proteasome inhibitor. In vivo binding of SAG and Skp2, an F-box protein that promotes p27 ubiquitination, was detected, and the binding was enhanced in SAG-overexpressing cells grown under serum starvation. Thus, SAG-induced growth with serum withdrawal appears to be associated with SAG-mediated p27 degradation. Mol. Carcinog. 30:37-46, 2001.
Mol Carcinog 2001 Jan
PMID:Promotion of S-phase entry and cell growth under serum starvation by SAG/ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation. 1125 62

Sensitive-to-apoptosis gene (SAG)/regulator of cullins (ROC)2/Rbx2/Hrt2 is a newly identified component of SCF E3 ubiquitin ligase that controls cell-cycle progression by promoting ubiquitination and degradation of cell-cycle inhibitors. We recently found that SAG protects cells from apoptosis induced by redox agents, promotes S-phase entry and cell growth under serum starvation, and is required for yeast growth. In the present study, we report that the SAG protein level was elevated in six of 10 human colon carcinoma tissues (60%) as compared with adjacent normal tissues from the same patient. SAG overexpression in preneoplastic cells in a JB6 tumor promotion-and-progression model did not induce neoplastic transformation, and SAG overexpression in NIH/3T3 cells did not induce transforming foci formation, suggesting that SAG is not a dominant oncogene. However, when DLD-1 human colon carcinoma cells were transfected with antisense SAG, monolayer growth was significantly inhibited, as shown by a decreased number of stable colonies in the plate after normalization with transfection efficiency. Stable clones that expressed antisense SAG showed a 50% decrease in their ability to form colonies when grown in soft agar versus clones that did not express antisense SAG. We found an inverse correlation in four of 10 tumors between the levels of SAG and p27, a cyclin-dependent kinase inhibitor. We concluded that SAG is not causally related to cellular transformation, but its overexpression may be important for the maintenance of tumor cell phenotype. Therefore, targeting SAG expression may have therapeutic value in cancer treatment. Mol. Carcinog. 30:62-70, 2001.
Mol Carcinog 2001 Jan
PMID:Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growth. 1125 65

beta-Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that beta-lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that beta-lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold beta-lapachone-induced increase in H(2)O(2) production seen in HL-60 cells, only a 2- to 4-fold increase was observed in HPC cells. N-acetyl-L-cysteine (NAC), a thiol antioxidant, inhibited the apoptosis in DU145 cells after 12 h exposure to beta-lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to beta-lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in beta-lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by beta-lapachone. According to our results, beta-lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. beta-Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21(WAF1) and p27(Kip1)), induces bak expression, and subsequently stimulates the activation of caspase-7 but not of caspase-3 or caspase-8 during the apoptosis of HPC cells. Taken together, these results suggest that the signaling pathway involving the beta-lapachone-induced apoptosis of HPC cell may be by DNA damage, induction of cdk inhibitors (p21 and p27), and then subsequent stimulation of caspase-7 activation.
Mol Pharmacol 2001 Apr
PMID:Induction of CDK inhibitors (p21(WAF1) and p27(Kip1)) and Bak in the beta-lapachone-induced apoptosis of human prostate cancer cells. 1125 23

In the differentiation of a myelomonocytic cell line U937 treated with 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2-D3], transient proliferation was observed prior to cell growth arrest. The expression of the p21 and p27 genes increased transiently and decreased quickly in the proliferation, suggesting that other genes may contribute to the growth arrest of the cell line after reduction of the p21 and p27 genes. The mac25 gene was isolated as a gene associated with cellular senescence and growth suppression. Despite a previous report that retinoic acid (RA) induced the mac25 gene, the mac25 gene did not increase in U937 cells treated with RA but did increase in the cells treated with 1alpha,25(OH)2-D3. The high level of the expression of the mac25 gene was detected for four days after the 1alpha,25(OH)2-D3 treatment. Therefore, mac25 may contribute to the growth arrest of U937 cells treated with 1,25-D3. The growth responses to 1alpha,25(OH)2-D3 and the expression of the mac25 gene of three other cancer cell lines (Saos-2, U2OS and MCF7) were studied. Although the growth suppression was observed in MCF7 cells treated with 1alpha,25(OH)2-D3 dose-dependently (1-100 nM of 1alpha,25(OH)2-D3), the treatment of 100 nM of 1alpha,25(OH)2-D3 had no effect on the growth of Saos-2 and U2OS cells. The expression of the mac25 gene was up-regulated in MCF7 cells treated with 100 nM of 1alpha,25(OH)2-D3, whereas no transcript of the mac25 gene was detected in Saos-2 and U2OS cells even when they were treated with 100 nM of 1alpha,25(OH)2-D3. These results suggest that the cellular response to 1alpha,25(OH)2-D3 may depend on the induction of the mac25 gene.
Int J Mol Med 2001 May
PMID:Correlation between induction of the mac25 gene and anti-proliferative effects of 1alpha,25(OH)2-D3 on breast cancer and leukemic cells. 1129 14

Strong expression of human epidermal growth factor receptor 2 (HER-2)/neu in breast cancer has been associated with poor prognosis. Reduced expression of p27(Kip1), a cyclin-dependent kinase inhibitor, correlates with poor clinical outcome in breast cancer. In this study, we provide a correlation between these two important prognostic markers in patients with breast cancer. Breast tumor screening using immunohistochemistry indicated that downregulation of p27 correlated with HER-2/neu overexpression in studying 11 normal breast tissues and 51 primary breast carcinomas. We found HER-2/neu protein overexpression in 20 (41%) of 49 breast cancers and low p27 protein expression in 47 (92%) of 51 breast cancers. All 20 (100%) of the tumors that overexpressed HER-2/neu had low levels of p27 protein product; this correlation was statistically significant (P = 0.035). Decreasing p27 expression correlated with increasing HER-2/neu activity. Our results suggest that one function of the HER-2/neu product is to downregulate p27 expression in breast cancer. This study may be significant in selecting patients for HER-2/neu antibody therapy in the future. Mol. Carcinog. 30:169--175, 2001.
Mol Carcinog 2001 Mar
PMID:Correlation of p27 protein expression with HER-2/neu expression in breast cancer. 1130 77

Androgens control both growth and differentiation of the normal prostate gland. However, the mechanisms by which androgens act upon the cell cycle machinery to regulate these two fundamental processes are largely unknown. The cyclin-dependent kinase (cdk) inhibitor p27 is a negative cell cycle regulator involved in differentiation-associated growth arrest. Here, we investigate the role and regulation of p27 in the testosterone proprionate (TP)-stimulated regeneration of the ventral prostate (VP) of castrated rats. Continuous TP administration to castrated rats triggered epithelial cell proliferation, which peaked at 72 h, and then declined despite further treatment. Castration-induced atrophy of the VP was associated with a significant increase in p27 expression as compared with the VP of intact animals. Twelve hours after the initiation of androgen treatment, total p27 levels as well as its fraction bound to cdk2, its main target, significantly dropped in the VP of castrated rats. Thereafter, concomitantly to the induction of epithelial cell proliferation, the glandular morphology of VP was progressively restored at 48-96 h of TP treatment. During this period of the regenerative process, whereas both proliferating basal and secretory epithelial cells did not express p27, the protein was selectively up-regulated in the nonproliferating secretory epithelial compartment. This up-regulation of p27 expression was coincident with an increase in its association with, and presumably inhibition of, cdk2. At each time point of TP treatment, p27 abundance in the VP was inversely correlated with the level of its proteasome-dependent degradation activity measured in vitro in VP lysates, whereas only slight changes in the amount of p27 transcripts were detected. In addition, the antiandrogen flutamide blocked maximal TP-induced p27 degradation completely. Finally, the expression of skp2, the ubiquitin ligase that targets p27 for degradation, was seen to increase with androgen administration, preceding maximal proliferation and concomitantly to augmented p27 degradation activity. Taken together, our data indicate that androgens mediate both proliferation and differentiation signals in normal prostate epithelial cells in vivo, through regulation of p27.
Mol Endocrinol 2001 May
PMID:Androgen-driven prostate epithelial cell proliferation and differentiation in vivo involve the regulation of p27. 1132 57

During the early process of skeletal muscle differentiation, myogenic factors are not only involved in muscle-specific gene induction but also in regulating the transition from the proliferative stage, when MyoD and Myf5 are already expressed, to the orderly exit from the cell division cycle. This key step in skeletal muscle differentiation involves the down-regulation of cell cycle activators such as cyclins and cdks, and up-regulation of cell cycle inhibitors such as Rb, p21, p27, and p57. In particular, Rb and p21 have been shown to play an important role in the growth arrest of differentiating myoblasts. Their level and/or activity, while being negatively controlled by growth factors, appear to be positively linked with the myogenic factor MyoD, which plays a cooperative role in the induction of growth arrest. MyoD can block proliferation independently of its transcriptional activity. Therefore, the interplay between G1 cyclins and cdk inhibitors, on the one hand, and MyoD and its co-factors, on the other, plays a critical role in myoblast cell cycle withdrawal. Accurate synchronization of dividing myoblasts revealed that MyoD and Myf5 are themselves subject to specific cell cycle-dependent regulation, with MyoD at its highest level in early G1 and its lowest level at the G1 to S phase transition. The time-window when cells exit their cycle into differentiation is in G1, when MyoD is maximal and Myf5 is down. In contrast, quiescent non-differentiating myoblasts (i. e., in G0) present an opposite pattern for the two factors: high Myf5 and no MyoD. Several recent studies have focused on MyoD phosphorylation and its potential role in ubiquitination-mediated degradation of the protein. Linking this phosphorylation to the cell cycle-dependent drop in MyoD protein before S phase leads, to a mechanism implying cdk2-cyclin E and its inhibitors (p57kip and p21cip) in the tight control of MyoD levels and subsequent myoblast cell cycle progression or exit into differentiation.
Cell Mol Life Sci 2001 Apr
PMID:Crosstalk between cell cycle regulators and the myogenic factor MyoD in skeletal myoblasts. 1136 Oct 92


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