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)

Boswellic acids are the compounds isolated from the gum resin of Boswellia serrata and have been used for the treatment of inflammatory diseases for many years in the countries of the east. Recently, a few studies showed that the acids may have anti-cancer effect on leukemia and brain tumours. We investigated the apoptotic and anti-proliferative effects of two types of boswellic acids, keto-beta-boswellic acid and acetyl-keto-beta-boswellic acid, on liver cancer Hep G2 cells. After treating the cells with the boswellic acids, cell proliferation, DNA synthesis, and apoptosis were analysed. The activities of caspase-3, -8 and -9 were assayed. To explore the apoptotic pathway, specific caspase inhibitors were employed. It was found that boswellic acids decreased cell viability and [3H]thymidine incorporation, checked the cells in the G1 phase, and increased percentage of sub-G1. Boswellic acids strongly induced apoptosis accompanied by activation of caspase-3, -8 and -9. The apoptosis was blocked completely by caspase-8 or caspase-3 inhibitor, but inhibited partly by caspase-9 inhibitor. However, these caspase inhibitors did not show any effect on the alternations of cell viability caused by boswellic acids. In conclusion, boswellic acids have anti-proliferation and anti-cancer effects on Hep G2 cells. The apoptotic effect is mediated by a pathway dependent on caspase-8 activation. The acids may be a promising drug for the chemoprevention of liver cancer.
Int J Mol Med 2002 Oct
PMID:Keto- and acetyl-keto-boswellic acids inhibit proliferation and induce apoptosis in Hep G2 cells via a caspase-8 dependent pathway. 1223 1

Farnesyltransferase inhibitors (FTIs) block the growth of tumor cells in vitro and in vivo with minimal toxicity toward normal cells. In general, inhibition of protein farnesylation results in G0/G1 cell cycle block, G2/M cell cycle arrest, or has no effect on cell cycle progression. One aspect of FTI biology that is poorly understood is the ability of these drugs to induce cancer cell growth arrest at the G2/M phase of cell cycle. In the present study, we investigated the effects of the farnesyltransferase inhibitor FTI-277 on two human liver cancer cell lines, HepG2 and Huh7. Treatment of these cells with FTI-277 inhibited Ras farnesylation in a dose-dependent manner. Both HepG2 and Huh7 cell growth was inhibited by FTI-277 and cells accumulated at the G2/M phase of the cell cycle. In HepG2 and Huh7 cells, FTI-277 induced an up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) without affecting the cellular levels of p53 and p21(Waf1). This event correlated with reduced activity of the cyclin-dependent kinase 2 and cyclin-dependent kinase 1. Moreover, increased expression of Bcl-2 protein was observed in HepG2 and Huh7 cells treated with FTI-277, and this was coincidental with reduced association between Raf-1 and Bcl-2. Finally, transient transfection of a dominant-negative Ras allele induced Bcl-2 expression and reduced Bcl-2/Raf-1 association demonstrating a requirement for Ras. Taken together, these findings show that increased expression of p27(Kip1) and Bcl-2 is concomitant with altered association between Ras, Raf-1 and Bcl-2 and suggest that this is responsible for the growth-inhibitory properties of FTI-277.
Mol Pharmacol 2003 Jan
PMID:Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2 expression and defective association with Raf-1 in liver cancer cell lines. 1248 48

Livers from wild-type and p53-deficient mice were analyzed for the expression of cell-cycle regulatory proteins in an attempt to determine the mechanism for the increased proliferation of liver cells in p53-deficient mice associated with enhanced susceptibility to aflatoxin-induced liver cancer. The most striking difference found was a significant reduction of the cyclin-dependent kinase inhibitor p27(kip1) in the livers of 3-mo-old p53-/- mice, whereas only small changes were found in the expression of cyclins, cyclin-dependent kinases, and the inhibitors p21(cip1) and p16(ink4a). Relative to wild-type liver, the amounts of p27(kip1) mRNA were reduced at both 1 and 3 mo, whereas the levels of p27(kip1) protein were decreased only at 3 mo. These results identify an uncharacterized link between the expression of p53 and p27(kip1) that may involve both transcriptional and post-transcriptional regulation and allow hepatocytes to continue to proliferate after 3 wk of age. We postulate that this increased proliferation leads to increased susceptibility to aflatoxin-induced hepatocarcinogenesis.
Mol Carcinog 2003 Jan
PMID:Reduced expression of p27kip1 and increased hepatocyte proliferation in p53-deficient mice. 1250 75

Cancer prevention is a challenging project both in the basic and clinical medicine. In particular, prevention of liver cancer is the most urgent task in countries where the incidence of hepatitis virus- related liver cancer is rising. As reviewed in this article, liver cancer is going to be the first cancer that will be actually prevented by primary and secondary interventions. Even the improvement of absolute survival of the patients can be expected by successful prevention, as already demonstrated in a few clinical trials. Thus, prevention of liver cancer is promising to provide not only cost-effectiveness by morbidity reduction but also cost-benefit by mortality improvement.
Exp Mol Med 2002 Nov 30
PMID:Prevention of liver cancer: basic and clinical aspects. 1252 94

DNA amplification in cancer cells frequently involves oncogenes whose increased expression confers a selective advantage on tumor cell growth. In an attempt to identify novel oncogenes involved in hepatocarcinogenesis, representational difference analysis (RDA) was performed using DNA from a primary human hepatocellular carcinoma (HCC) that showed high-level DNA amplifications on chromosomes 1p32 and 11q13 by comparative genomic hybridization. Ten amplification fragments were isolated by RDA, and when used to probe Southern blots of tumor DNA, there was a 5- to 50-fold increase in hybridization intensity relative to normal DNA. The sequence of one amplification product matched that of the EMS1 oncogene, which is located on chromosome 11q13 and is amplified in other cancers. We detected EMS1 amplification in 3 of 17 primary HCC. Overexpression of EMS1 mRNA was observed in 12 of 14 HCC cell lines in the absence of gene amplification or an increased copy-number of the gene. The EMS1 gene encodes cortactin, a cortical actin-associated protein that is a substrate for Src kinase and is involved in cytoskeleton organization. Alterations of the EMS1 gene that lead to overexpression of cortactin may be associated with tumor development in HCC. EMS1 amplification and overexpresion is indicative of unfavorable prognosis in several cancers and may have similar prognostic implications in liver cancer.
J Mol Diagn 2003 Feb
PMID:Amplification and overexpression of the EMS 1 oncogene, a possible prognostic marker, in human hepatocellular carcinoma. 1255 80

We have previously mapped a liver tumor suppressor locus to human chromosome 11p11.2-p12 using a functional model of tumor suppression. Using this model system, we have employed a candidate gene approach to identify potential liver tumor suppressor genes. Thirty-eight known genes have been positioned in human 11p11.2-p12 by the Human Genome Project. Here we show that four of these genes (guanine nucleotide binding protein gamma 3; mitochondrial carrier homolog 2; p53-induced protein (PIG11), and pRDI-BF1-rIZ1 domain containing 11) localized to the minimal liver tumor suppressor region within 11p11.2-p12. In fact, all of these genes mapped to human 11p11.2, allowing refinement of the liver tumor suppressor region to this cytogenetic band. Three of the four genes (mitochondrial carrier homolog 2, PIG11, and pRDI-BF1-rIZ1 domain containing 11) were uniformly expressed by an index panel of suppressed microcell hybrid cell lines, identifying them as candidate liver tumor suppressor genes. In a preliminary analysis of four human hepatocellular carcinoma cell lines (HepG2, Hep3B, SNU398, and SNU449), the transcript for PIG11 was lost or significantly decreased in two of these cell lines (HepG2 and Hep3B), suggesting the potential involvement of PIG11 in some human hepatocellular carcinomas. The results of this study extended our previous knowledge of genes located in the minimal liver tumor suppressor region of human 11p11.2 and identified several candidate liver tumor suppressor genes from this region. Further characterization of these candidates will provide new insight into the role of human 11p11.2 in the molecular pathogenesis of human liver cancer.
Mol Carcinog 2003 Feb
PMID:Identification of three 11p11.2 candidate liver tumor suppressors through analysis of known human genes. 1255 65

Insulin-like growth factor binding protein-1 (IGFBP-1) is synthesized in the liver and regulates the mitogenic effects of the insulin-like growth factors (IGFs). The evidence that IGFBP-1 plays a role in hepatocarcinogenesis, however, is equivocal. We have, therefore, investigated the development of preneoplastic hepatic lesions in transgenic mice in which the human IGFBP-1 gene is under the control of the mouse metallothionein promoter. The lesions were induced by treating 15-d-old male mice with a single intraperitoneal injection of 5 mg/kg diethylnitrosamine (DENA). Lesions were scored when the mice were 28 wk of age. Quantitative microscopy of liver sections revealed that significantly fewer transgenic mice treated with zinc to activate the transgene had focal lesions compared to either transgenic mice not treated with zinc or wild-type mice treated with zinc (36.4% versus 85.7% and 83.3%, respectively, P < 0.05 in each case). Zinc-treated transgenic mice also had significantly fewer lesions per liver (11.5 +/- 5.0 versus 74.7 +/- 18.4 and 59.4 +/- 15.6, respectively, P < 0.01 in each case) and a smaller percentage of liver volume occupied by lesions (0.2 +/- 0.1 versus 1.4 +/- 0.3 and 1.1 +/- 0.4 respectively, P < 0.05 in each case). Immunohistochemical staining showed that both IGF-I and IGF-II were overexpressed in most of the lesions. These results show that expression of the IGFBP-1 transgene leads to a marked inhibition of hepatic preneoplasia, possibly by decreasing the mitogenic activity of IGF-I and/or IGF-II. This study adds new evidence to the notion that the IGF axis plays an important role in liver cancer development.
Mol Carcinog 2003 Mar
PMID:Insulin-like growth factor binding protein-1 over-expression in transgenic mice inhibits hepatic preneoplasia. 1261 36

Hepatitis C virus (HCV) is a leading cause of liver cancer and cirrhosis, and Egypt has possibly the highest HCV prevalence worldwide. In this article we use a newly developed Bayesian inference framework to estimate the transmission dynamics of HCV in Egypt from sampled viral gene sequences, and to predict the public health impact of the virus. Our results indicate that the effective number of HCV infections in Egypt underwent rapid exponential growth between 1930 and 1955. The timing and speed of this spread provides quantitative genetic evidence that the Egyptian HCV epidemic was initiated and propagated by extensive antischistosomiasis injection campaigns. Although our results show that HCV transmission has since decreased, we conclude that HCV is likely to remain prevalent in Egypt for several decades. Our combined population genetic and epidemiological analysis provides detailed estimates of historical changes in Egyptian HCV prevalence. Because our results are consistent with a demographic scenario specified a priori, they also provide an objective test of inference methods based on the coalescent process.
Mol Biol Evol 2003 Mar
PMID:The epidemiology and iatrogenic transmission of hepatitis C virus in Egypt: a Bayesian coalescent approach. 1264 58

The pattern of transcriptional activation by 17beta-estradiol (E2) and 4-hydroxytamoxifen (4-OHT) was determined in ZR-75 and MDA-MB-231 breast, ECC1 and HEC1A endometrial and HepG2 liver cancer cell lines cotransfected with E2-responsive constructs and wild-type estrogen receptor alpha (ER alpha) or ER beta (ER beta) or variant forms of ER alpha expressing activation function 1, AF1 (ER alpha-AF1) or activation function 2, AF2 (ER alpha-AF2). The E2-responsive constructs contained promoter inserts from the human complement C3 (pC3), human cathepsin D (pCD) and rat creatine kinase B (pCKB) genes. Minimal ER beta-dependent transactivation (<2.5-fold induction) was observed for E2 only in ECC1 and MDA-MB-231 cells transfected with pCKB or pC3, whereas 4-OHT was inactive as an ER beta agonist for all promoters in the four cell lines. The ER alpha agonist and/or antagonist activities for E2 and 4-OHT were highly variable and the transactivation was dependent on ER subtype, ER alpha variant expressed, gene promoter, and cell context. For example, E2 did not activate pCD in HepG2 cells transfected with wild-type or variant ER alpha, whereas E2 activated reporter gene activity in the four endometrial and breast cancer cell lines transfected with ER alpha and pCD, pCKB or pC3. Hormone activation of these constructs by ER alpha-AF1 or ER alpha-AF2 was highly variable among the different cell lines and even in the same cell line transfected with the three E2-responsive constructs. Similar variability was observed for 4-OHT. For example, 4-OHT activates pC3 in HepG2 cells transfected with ER alpha or ER alpha-AF1, and pCKB in HEC1A cells. However, AF1-dependent activation by 4-OHT is not observed for pCKB in ECC1 cells or for pC3 and pCD in HEC1A or ECC1 endometrial cancer cells. The results of this study suggest that transcriptional activation by E2 and 4-OHT induces recruitment of different transcription factor complexes that are dependent on the cell type and also the gene promoter.
J Steroid Biochem Mol Biol 2003 Jan
PMID:17 beta-estradiol- and 4-hydroxytamoxifen-induced transactivation in breast, endometrial and liver cancer cells is dependent on ER-subtype, cell and promoter context. 1264 21

Sequence-specific small interfering RNA (siRNA) duplexes can be used for gene silencing in mammalian cells and as mechanistic probes for determining gene function. Transfection of siRNAs for the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) mRNAs in MCF-7 breast cancer cells resulted in a 60 to 80% decrease in levels of AhR and ARNT proteins in whole-cell extracts and decreased binding of nuclear extracts to 32P-labeled dioxin-responsive element. siRNA for the AhR also decreased 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 protein, CYP1A1-dependent activity, and luciferase activity in cells transfected with an Ah-responsive construct. 17beta-estradiol (E2) induces proliferation of MCF-7 cells through enhanced G0/G1 --> S phase progression, and this response is inhibited in cells cotreated with E2 plus TCDD. The effects of TCDD on E2-induced cell-cycle progress were partially blocked in MCF-7 cells transfected with siRNA for AhR. The results also indicated that siRNA-dependent decreases in AhR protein in MCF-7 cells were accompanied by increased G0/G1 --> S phase progression, suggesting a growth-inhibitory role for the "endogenous" AhR. Surprisingly, TCDD alone induced G0/G1 --> S phase progression and exhibited estrogenic activity in MCF-7 cells transfected with siRNA for the AhR. In contrast, degradation of the AhR in HepG2 liver cancer cells resulted in decreased G0/G1 --> S phase progression, and this was accompanied by decreased expression of cyclin D1, cyclin E, cyclin-dependent kinase 2 (cdk2), and cdk4. In the absence of ligand, the AhR exhibits growth-inhibitory (MCF-7) and growth-promoting (HepG2) activity that is cell context-dependent.
Mol Pharmacol 2003 Jun
PMID:Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells. 1276 48


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