UNIPROT:P10415 - FACTA Search

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

Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

E1A + c-Ha-ras-transformants overexpressing bcl-2 oncogene are able to be arrested at the G1/S boundary of the cell cycle after DNA damage and upon serum starvation, this cell cycle blockage being accompanied by a decrease in the activity of cyclin E--Cdk2 complexes. Roscovitine-induced inhibition of cyclin-dependent kinases (Cdks) activity does not result in the G1/S arrest of E1A + c-Ha-ras + bcl-2-transformants. Roscovitine treatment causes an accumulation of G2/M cells, mainly at the expense of mitotic cells. However, the expression of Bcl-2 oncoproducts does not re-establish the regulation of mitotic events broken by introduction of E1A and c-Ha-ras oncogenes in normal cells, as revealed by the treatment of E1A + c-Ha-ras + bcl-2-transformants with nocodazole inducing mitotic arrest in normal cells. In spite of the elevated expression of antiapoptotic bcl-2 gene in transformants, nocodazole treatment results in mass apoptotic death preceded by polyploidy. Roscovitine also induces apoptosis with no polyploid cell accumulation being observed. Inhibition of Cdks activity with Roscovitine, as well as violation of microtubule depolymerization with nocodazole result in the apoptotic death in the tested cell lines sensitive (E1A + c-Ha-ras) and resistant (E1A + c-Ha-ras + bcl-2) to damaging agents. Thus, the application of Roscovitine, a specific inhibitor of Cdks, suggests that the decrease in Cdks activity in E1A + c-Ha-ras + bcl-2-transformants is not likely to be responsible for G1/S cell cycle arrest realization after damaging influences. Moreover, an antiproliferative effect of Bcl-2 in E1A + c-Ha-ras-transformants is restricted by restoration of cell cycle events at G1/S and G2/M boundaries, and does not concern the program of mitotic events regulation.
...
PMID:[Antiproliferative effect of bcl-2 gene does not concern the control of mitotic events]. 1521 71

The highly controlled degradation of proteins via the ubiquitin-proteasome pathway represents a key mechanism for cell regulation and homeostasis. Ubiquitin-dependent proteolysis, carried out in large part by the E3 ubiquitin ligases, is a critical mode of post-translational modification that is important in regulation of cell cycle progression, signal transduction, gene transcription, antigen receptor signaling, immune response and cell differentiation. Recent studies demonstrate that increasing numbers of proteins with ubiquitin ligase activity are being characterized. Identification and characterization of their substrates indicate that they regulate the turnover of key cell cycle proteins (p27Kip1, p21Cip1, p57Kip2, cyclin E), tumor suppressor proteins (p53, RB), signaling kinases (Src, Zap70, PI-3 kinase), apoptosis regulators (Bcl-2, Bax, Bik) and transcription factors (Myc, NF-kappaB, E1F1), all of which have been implicated in the pathogenesis of malignant lymphoma. Studies to determine the functional role of ubiquitin ligases in the pathogenesis of malignant lymphoma represent potential areas of investigation.
...
PMID:Ubiquitin ligases in malignant lymphoma. 1535 30

Here we show that introduction of human bcl-2 gene into E1A+c-Ha-ras-transformed rat embryo fibroblasts, which are highly susceptible to proapoptotic stimuli and fail to be arrested at the G(1)/S boundary following genotoxic stresses, results not only in inhibition of apoptosis, but also in restoration of the G(1)/S arrest. Overexpression of Bcl-2 did not affect proliferation rate and saturation density of E1A+c-Ha-ras transformants. Genotoxic stresses caused prolong G(1)/S arrest in Bcl-2-overexpressing transformants. Remarkably, levels and activities of Cdk2, cyclins E/A, cyclin E-Cdk2 and cyclin A-Cdk2 were unchanged during G(1)/S arrest. Introduction of Bcl-2 into E1A+c-Ha-ras-transformants resulted in accumulation of p21/Waf-1 without inhibiting cyclin-Cdk complexes. In both parental and Bcl-2-overexpressing cells, p21/Waf-1 was coimmunoprecipitated with ERK 1,2 and JNK 1,2, whereas p38 was found in complexes with p21/Waf-1 only in Bcl-2-overexpressing transformants. JNK 1,2 and p38 but not ERK 1,2 were detected in complexes with the exogenous Bcl-2. However, Bcl-2 did not affect phosphorylation of ERK 1,2, JNK 1,2 and p38. G(1)/S arrest induced by adriamycin and serum withdrawal (but not by IR) was accompanied by release of active forms of p38 from complexes with Bcl-2. We suggest that Bcl-2 restores stress-induced G(1)/S arrest without inhibiting cyclin-Cdk2 complexes and MAPK pathways.
...
PMID:Restoration of G1/S arrest in E1A+c-Ha-ras-transformed cells by Bcl-2 overexpression. 1549 6

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
...
PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

The effect of conjugated docosahexaenoic acid (CDHA) on the inhibition of colon cancer cell growth was examined in the colo 201 human colon cancer cell line, and the effect was compared with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). CDHA was a more potent tumor cell growth inhibitor than DHA and EPA by colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay (IC50 for 72 h: 31.6 microM, 46.8 microM, and 56.6 microM, respectively). CDHA inhibited cell cycle progression, due to accumulation of cells in G1 phase, which involved increased p21Cip1/Waf1 and decreased cyclin D1, cyclin E, and proliferating cell nuclear antigen expression; the p53 and cyclin A levels were unchanged. Induction of apoptosis was confirmed by the appearance of sub-G1 populations, and apoptosis cascade involved upregulation of the apoptosis-enhancing proteins (Bak and Bcl-xS) and downregulation of the apoptosis-suppressing proteins (Bcl-xL and Bcl-2). CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins, similar to the effects of DHA. CDHA at a dietary dose of 1.0% significantly inhibited growth of colo 201 cells transplanted in nude mice.
...
PMID:Conjugated docosahexaenoic acid is a potent inducer of cell cycle arrest and apoptosis and inhibits growth of colo 201 human colon cancer cells. 1557

Sodium butyrate is a short-chain fatty acid produced by fermentation in the gastrointestinal tract. It induces differentiation of several kinds of cancer by inhibiting histone deacetylase activity. We have reported that butyrate stimulates hepatocellular carcinoma cells into their normal phenotype. Since sodium butyrate affects both differentiation and apoptosis, we investigated expression of bcl-2-related genes in a human hepatocellular carcinoma cell line HCC-T. The expression of anti-apoptotic Bcl-2 and Mcl-1/EAT was up-regulated 4 h after the treatment, while pro-apoptotic Bax expression did not change. Gene expressions in the early stage of butyrate-stimulation were investigated by the differential display assay and the cDNA expression array. Laminin and keratin 18 were increased 6 h after the stimulation with sodium butyrate. The results of cDNA expression array revealed up-regulation of cell cycle inhibitory genes such as cyclin-dependent kinase 4 inhibitor, and interferon-related genes such as STAT2 and 3, while down-regulation of cyclin-dependent kinase 2 and cyclin E. Up-regulated production of p21WAF-1 and Mcl-1/EAT was also confirmed by Western blotting. The cytoskeletal change indicated by up-regulation of laminin and keratin 18 may be an important factor in the decrease in malignant phenotype of cancer cells. Up-regulation of interferon-related genes indicated that butyrate-treatment might induce a similar phenotypic change to that induced by type 1 interferons. This study suggests several target genes for the future gene therapy of cancer or genes preventing cancer development from pre-malignant tissues.
...
PMID:Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor. 1558 45

S-phase kinase associated protein (Skp) 2 is an F-box protein required for substrate recognition of the SCF(Skp2) ubiquitin ligase complex. Skp2 is often overexpressed in transformed cells and in various types of tumors. Downregulation or inhibition of Skp2 inhibits growth of breast cancer cells and small-cell lung carcinoma cells. We downregulated Skp2 in T98G glioblastoma cells using small interfering RNA (siRNA). Downregulation induced p27 and caused growth arrest and apoptosis. Downregulation of both Skp2 and p27 increased apoptosis synergistically. Cyclin E levels and cyclin E-CDK2 kinase activity increased dramatically when both Skp2 and p27 were downregulated. Coincidently, Bcl-2 but not Bcl-xL expression decreased, and caspase-3 was activated. Inhibition of cyclin E-CDK2 kinase activity by forced expression of p21 reversed these effects. Moreover, stable expression of Bcl-2 also abrogated apoptosis induced by downregulation of Skp2 and p27. We suggest that Skp2 in tumor cells suppresses apoptosis through Bcl-2 expression, potentially through regulation of cyclin E-CDK2 activity.
...
PMID:Downregulation of Skp2 and p27/Kip1 synergistically induces apoptosis in T98G glioblastoma cells. 1560 73

Enchondromas and conventional central chondrosarcomas are, respectively, benign and malignant hyaline cartilage-forming tumours that originate in the medulla of bone. In order to gain a better understanding of the molecular process underlying malignant transformation of enchondroma, and to investigate whether there is a biological difference between conventional central cartilaginous tumours and those of enchondromatosis or with phalangeal localization, a series of 64 enchondromas (phalanx, n = 21; enchondromatosis, n = 15) and 89 chondrosarcomas (phalanx, n = 17; enchondromatosis, n = 13) was collected. Indian Hedgehog (IHH)/parathyroid hormone related peptide (PTHrP) signalling, an important pathway in chondrocyte proliferation and differentiation within the normal growth plate, was studied by immunohistochemical analysis of the expression of PTHrP, PTHR1, Bcl-2, p21, cyclin D1, and cyclin E. Quantitative real-time PCR for IHH, PTCH, SMO, and GLI2 was performed on a subset of tumours. The data show that IHH signalling is absent in enchondromas and central chondrosarcomas, while PTHrP signalling is active. There was no difference in the expression of any of the molecules between 35 enchondromas and 26 grade I central chondrosarcomas, indicating that PTHrP signalling is not important in malignant transformation of enchondroma. Higher expression of PTHR1 and Bcl-2 was associated with increasing histological grade in chondrosarcoma, suggesting involvement in tumour progression. No difference was found between samples from enchondromatosis patients and solitary cases, suggesting no difference in PTHrP signalling. A small subset of phalangeal chondrosarcomas demonstrated down-regulation of PTHrP, which may be related to its more indolent clinical behaviour. Thus, in both enchondromas and central chondrosarcomas, PTHrP signalling is active and independent of IHH signalling, irrespective of the presence or absence of enchondromatosis.
...
PMID:Absence of IHH and retention of PTHrP signalling in enchondromas and central chondrosarcomas. 1568 1

The initial aim of this study was to examine the expression profiles of P53 and its upstream genes, downstream genes, and cell cycle regulators to determine whether these markers are useful for making a differential diagnosis among the benign, borderline, and malignant ovarian epithelial tumors. Between borderline and malignant tumors, the increased expression levels of P53, Bax, Cyclin E, and cyclin-dependent kinase-2 as well as the decreased expression levels of growth arrest and DNA damage (GADD45) and murine double minute-2 (MDM2) were significantly associated with malignancy (P < 0.01, each). Using the receiver operating curve (ROC), the most reliable cutoff value of the added-up staining scores of those markers was 4.5 with 79% sensitivity and 89% specificity for malignancy. Between benign and borderline tumors, the P21 and Bax expression levels were significantly higher in borderline tumors, whereas the Bcl-2 expression level was much higher in benign tumors (P < 0.01, each). Using the ROC, the cutoff value of the added-up staining scores used to discriminate between the two groups was 2.5 with 70% sensitivity and 74% specificity for borderline tumors. Thus, for the differential diagnosis between borderline and malignant tumors, the cutoff value 4.5 of the cumulative staining scores can be used. However, the cutoff value 2.5 for discrimination between benign and borderline tumors may not be useful because of its relatively low sensitivity and specificity. In addition, the P53, GADD45, Cyclin E, and MDM2 expression levels in malignant ovarian tumors might be useful for determining the histologic grade and type.
...
PMID:Diagnostic approach using the expression profiling of the P53 tumor suppressor gene and its related proteins in ovarian epithelial tumors. 1588 69

1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (I6), a gingerdione derivative, was synthesized in our laboratory, has been demonstrated to be an effective anti-tumor agent in human leukemia cells. Gingerdione is one of the components from ginger. In the present study, we found that I6 could inhibit cell proliferation in the time- and dose-dependent manner in human promyelocytic leukemia HL-60 cells. To investigate the anti-proliferation mechanism of I6, cell cycle analysis was performed. Results showed that I6 induced significant G1 arrest and apoptosis in HL-60 cells. It was proved by the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of regulatory on G1 arrest that the levels of p15 and p27 increased after treatment and mRNA levels of cyclin D2, cyclin E, and cdc25A were decreased. The I6-induced apoptosis was further confirmed by DNA fragmentation assay. The DNA gel electrophoresis showed that I6 induced DNA fragmentation, a biochemical hallmark of apoptosis, in HL-60 cells. I6-induced apoptosis was accompanied by an apparent up-regulation of caspase-3, and down-regulation of Bcl-2. Taken together, these results suggest that markedly down-regulation of G1 associated cyclin D2, cyclin E and cdc25A and up-regulation of CDKI, p15 and p27, and may contribute to I6-mediated cell cycle arrest. Furthermore, the Bcl-2 expression decrease and caspase-3 activation may be the plausible mechanism by which I6 induced apoptosis. These results suggest that I6 is a potent anti-HL-60 drug and possess a significant action on cell cycle before commitment for apoptosis occurrence.
...
PMID:1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (I6) induces G1 arrest and apoptosis in human promyelocytic leukemia HL-60 cells. 1592 54

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>