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

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymidylate synthase (TS) is thought to be one of the target genes that the E2F1 transcription factor binds to and regulates. However, the relationship between the expressions of TS and E2F1 in primary colon cancer specimens remains unclear. The aim of this study was to define the relation of TS and E2F1 gene expressions in tumor samples from 23 colon cancer patients. TS and E2F1 gene expressions were measured by TaqMan reverse transcription-PCR assay using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard and expressed as a TS:GAPDH or E2F1:GAPDH mRNA ratio. A close relationship was found between TS gene expression and E2F1 gene expression (r2 = 0.598, P < 0.001) in 23 tumor samples analyzed. Surprisingly, a high correlation between TS gene expression and E2F1 gene expression was observed even in advanced tumors from stage IV colon cancer patients. These results suggest that transcription of the TS gene may be regulated by E2F1 in primary colon cancer specimens and that this gene-regulatory pathway from E2F1 to TS may be highly conserved during malignant progression. Four of the 23 patients showed TS overexpression with increased E2F1 expression. These results suggest that the ability of a tumor to increase TS expression may possibly be due to an overexpression of E2F1. Although the number of patients was relatively small, our study provides new insights into the molecular mechanisms underlying the regulation of TS expression in colon cancers.
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PMID:Thymidylate synthase expression correlates closely with E2F1 expression in colon cancer. 1091 14

Despite the wide use of 5-fluorouracil (5-FU) for colon cancer, the genes regulating its cytotoxic effect are poorly understood. We used a high-density oligonucleotide microarray representing approximately 7000 genes to determine changes in gene expression caused by 5-FU treatment in the colon cancer cell line, SW620. The microarray showed that the most strongly up-regulated gene by 5-FU was vitamin D3 up-regulated protein 1 (VDUP1), an interesting stress response gene, which was originally reported as a vitamin D3 inducible gene in HL-60. TaqMan RT-PCR assay confirmed that VDUP1 gene expression was significantly increased after 24 h of 5-FU treatment compared with untreated control (p<0.01). Moreover, the expression of vitamin D3 receptor, thymidylate synthase (TS), and E2F1 did not change within 24 h of 5-FU treatment, suggesting a different gene-regulatory pathway from that of VDUP1. Recent studies have gradually clarified the potential role of VDUP1 via interaction with TRX in an anti-tumor effect. Therefore, VDUP1 not only may be induced by stress response as a result of 5-FU cytotoxicity, but may also play a key role in 5-FU cytotoxicity in colon cancers. Our experiment using a microarray and TaqMan RT-PCR assay, together with previous reports, provides new insight into a potential mechanism of 5-FU cytotoxicity.
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PMID:Up-regulation of vitamin D3 up-regulated protein 1 gene in response to 5-fluorouracil in colon carcinoma SW620. 1174 59

The E2F family plays a critical role in the expression of genes required for entry into and progression through S phase. E2F-mediated transcription is repressed by the tumor suppressor retinoblastoma protein (pRb), which results in sequestration of E2F in a multiprotein complex that includes pRb. Derepression of E2F results from a series of complex phosphorylation events mediated by cyclin D/cdk4 and cyclin E/cdk2. We have employed a novel 3-substituted indolinone compound, 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516), which selectively inhibits cdk2 activity (Lane et al., Cancer Res 2001;61:6170-7) to investigate these events. Electrophoretic mobility gel shift assays were performed on SU9516-treated and -untreated HT-29, SW480, and RKO human colon cancer cell extracts. Treatment with 5 microM SU9516 prevented dissociation of pRb from E2F1 in all cell lines (HT-29>RKO>SW480). Treatment effects were time-dependent, demonstrating greater inhibition at 48 hr versus 24hr in HT-29 cells. Furthermore, E2F species were sequestered in complexes with p107, p130, DP-1, and cyclins A and E. After a 24-hr treatment with 5 microM SU9516, cyclin D1 and cdk2 levels decreased by 10-60%. These findings delineate a previously undescribed mechanism for SU9516-mediated cell growth arrest through down-regulation of cyclin D1, inhibition of cdk2 levels and activity, and pan-sequestration of E2F.
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PMID:SU9516, a cyclin-dependent kinase 2 inhibitor, promotes accumulation of high molecular weight E2F complexes in human colon carcinoma cells. 1223 12

As previously demonstrated, deguelin [(7aS, BaS)-13, 13a-dihydro-9,10-dimethoxy-3,3-dimethyl-3H-bis[1]benzo-pyrano[3,4-b:6',5'-e]pyran-7(7aH)-one mediates anti-proliferative properties in a variety of cell types. In the present study, deguelin was found to suppress the growth of HT-29 colon cancer cells with an IC(50) of 4.32 x 10(-8) M. The cells were arrested in the G1-S-phase of the cycle. Investigations of G1/S regulatory proteins by Western blot analyses showed an upregulation of p27, and decreased expression levels of cyclin E and CDK4. Furthermore, by 24 h, exposure to deguelin resulted in an increase in the hypophosphorylated form of Rb. Since hypophosphorylated pRb binds to and inactivates E2F1, additional studies were performed and downregulation of E2F1 was observed after 24 h of treatment with deguelin. These results are consistent with the observation that deguelin arrested cells in the G1-S- phase. In addition, based on ethidium bromide/acridine orange staining, detection of digoxigenin-labelled genomic 3'-OH DNA ends, and DNA laddering, it was found that deguelin exerts its growth inhibitory effects via the induction of apoptosis. Based on these data, the potential of deguelin to serve as a cancer chemotherapeutic agent for colon cancer may be suggested.
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PMID:Deguelin inhibits the growth of colon cancer cells through the induction of apoptosis and cell cycle arrest. 1246 Jul 90

The specific mechanisms controlling the transition from proliferation to terminal differentiation in human intestinal epithelial cells (HIEC) remain largely undefined. Herein, we analyzed the expression and localization of Rb and E2F proteins in well-established normal intestinal epithelial cell models which allow for the re-enactment of the crypt-villus axis in vitro as well as in intact epithelium and in colon cancer cells. We report that (1) expression of E2F1 is down-regulated while E2F4 protein is sequestered in the cytoplasm during G(0) arrest associated with serum deprivation, confluency, and terminal differentiation of intestinal cells; (2) concurrently, there is an accumulation of the hypophosphorylated form of the pocket proteins into the nucleus with an increased association of E2F4 with pRb and p130; (3) cells which expressed high levels of nuclear E2F4 are all positive for Ki67 staining in human fetal intestine; (4) activation of HIEC crypt cells by growth factors leads to an increase in the nuclear localization of E2F4 which may be attributable to a decrease in the serine/threonine phosphorylation of this transcription factor; (5) inhibition of p38 MAP kinase with alpha/beta inhibitor SB203580 induces E2F4 translocation into the nucleus and its transcriptional activity. In conclusion, our data suggest a key role for E2F4 in proliferation of human intestinal crypt cells and that its cytoplasmic retention as well as its sequestration by Rb proteins may represent a critical step in initiating cell-cycle exit.
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PMID:The nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human intestinal epithelial cell proliferation and differentiation. 1504 9

MCM10 and TopBP1 function in the initiation of DNA replication, by regulating the chromatin binding of the DNA polymerase alpha loading factor, CDC45. TopBP1 is also known as a DNA damage response protein. In this study, we showed that the transcription of human MCM10 and TopBP1 is activated by transcription factors E2F1-3, but not by factors E2F4-7. Analysis of various MCM10 and TopBP1 promoter constructs showed that an E2F-responsive sequence in the vicinity of the transcription initiation site is necessary for the E2F1-induced activation of MCM10 and TopBP1 gene transcription, which is further suppressed by pRb. The promoter activities of human MCM10 and TopBP1 were demonstrated to be growth dependent via the E2F-responsive sequence. Although E2F1 was stabilized by ultraviolet (UV) irradiation, the mRNA expression level of TopBP1 was suppressed in HCT116 human diploid colon cancer cells. We showed, by performing chromatin immunoprecipitation that, in response to UV irradiation but not doxorubicin treatment, E2F4 accumulated on the MCM10 and TopBP1 promoters. Our data suggest a model in which UV irradiation-induced DNA damage depends, at least in part, on the accumulation of the E2F4 transcription factor on the MCM10 and TopBP1 promoters, which results in suppression of DNA replication.
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PMID:Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV irradiation via the E2F transcription factor. 1519 43

alpha-Tocopherol succinate (TS), an analogue of vitamin E, has growth-inhibitory activity in a wide spectrum of in vitro and in vivo cancer models. Here, we report that modulation of oncogenic Ras is associated with TS activity. TS inhibits the proliferation and induces apoptosis of NIH3T3 cells stably transfected with oncogenic K-Ras and H-Ras, but not NIH3T3 cells expressing empty vector. TS treatment resulted in decreased Ras protein levels in oncogenic Ras expressing NIH3T3 cells but not in parental NIH3T3 cells. Treatment with TS suppressed the levels of phospho-Akt and phospho-Erk1/2 in oncogenic Ras expressing NIH3T3 cells. Overexpression of constitutively active phosphoinositide-3-kinase, Akt, and Mek1/2 significantly attenuated TS growth inhibition of oncogenic Ras-transformed NIH3T3 mouse fibroblast cell lines. In addition, transcriptional targets of oncogenic Ras such as c-Myc, cyclin D1, and E2F1 were down-regulated by TS in oncogenic Ras-expressing cells. The above TS effects on oncogenic Ras signaling were also observed in endogenous oncogenic K-Ras expressing HCT 116 (human colon cancer) and MDA-MB-231 (human breast cancer) cells. Taken together, these data show that TS down-regulation of the Ras signaling pathways that are mediated by Mek/Erk and phosphoinositide-3-kinase/Akt plays, at least in part, a critical role in TS inhibition of proliferation and survival of transformed cells. This data supports further investigation of the chemopreventive and therapeutic potential of TS in tumors that are dependent on activated Ras signaling and identifies phosphor-Erk and phosphor-Akt as potential biomarkers of TS activity.
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PMID:RRR-alpha-tocopherol succinate down-regulates oncogenic Ras signaling. 1650 4

In our current study, we developed oncolytic adenoviruses which preferentially lyse pancreatic and colon cancer cells by replacing viral E1 and/or E4 promoter with the tumor/tissue-specific promoters, cyclooxygenase-2 (COX-2), midkine (MK), or the cell cycle-dependent promoter, E2F1. We generated three sets of recombinant adenoviral vectors. In the first set, only the native E1A promoter was replaced by the COX-2, MK, or E2F1 promoter, respectively. In the second set, the viral E4 promoter was substituted by these heterologous promoters and the viral E1A promoter was substituted by the ubiquitously active cytomegalovirus-IE promoter. In the third set, we substituted the viral E1A and E4 promoters with the COX-2, MK, or E2F1 promoter, respectively. In our system, transcriptional targeting of solitary viral E1A resulted in 50% enhanced restricted vector replication when compared with an unrestricted replication-competent adenovirus. Furthermore, a targeted expression of the viral E1A gene products had a greater effect on restricted adenoviral replication than that of the E4 region. With our vectors, Ad.COX.MK and Ad.MK.COX, using two different heterologous promoters to control E1A and E4 expression, we showed enhanced viral replication specificity when compared with Ad.COX.COX or Ad.MK.MK, respectively. In a s.c. xenograft tumor model, there was no significant difference in the antineoplastic efficacy of the double heterologous promoter-controlled vectors when compared with our unrestricted replication-competent control adenovirus or vectors with only E1A transcriptionally driven by a heterologous promoter.
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PMID:Restriction of adenoviral replication to the transcriptional intersection of two different promoters for colorectal and pancreatic cancer treatment. 1650 12

E2F transcription factors control cell cycle progression. The localization of E2F4 in intestinal epithelial cells is cell cycle dependent, being cytoplasmic in quiescent differentiated cells but nuclear in proliferative cells. However, whether nuclear translocation of E2F4 alone is sufficient to trigger intestinal epithelial cell proliferation remains to be established. Adenoviruses expressing fusion proteins between green fluorescent protein (GFP) and wild-type (wt)E2F4 or GFP and nuclear localization signal (NLS)-tagged E2F4 were used to infect normal human intestinal epithelial crypt cells (HIEC). In contrast to expression of wtE2F4, persistent expression of E2F4 into the nucleus of HIEC triggered phosphatidylserine exposure, cytoplasmic shrinkage, zeiosis, formation of apoptotic bodies, and activation of caspase 9 and caspase 3. Inhibition of caspase activities by zVAD-fmk partially inhibited cell death induced by E2F4-NLS. An induction of p53, phosphorylated Ser15-p53, PUMA, FAS, BAX, RIP, and phosphorylated JNK1 was also observed in HIEC expressing E2F4-NLS compared with wtE2F4-expressing cells. E2F1 and p14ARF expression remained unaltered. Downregulation of p53 expression by RNA interference attenuated cell death induced by E2F4-NLS. By contrast, the level of cell death was negligible in colon cancer cells despite the strong expression of E2F4 into the nucleus. In conclusion, deregulated nuclear E2F4 expression induces apoptosis via multiple pathways in normal intestinal epithelial cells but not in colon cancer cells. Hence, mutations that deregulate E2F4 localization may provide an initial proliferative advantage but at the same time accelerate cell death. However, intestinal cells acquiring mutations (e.g., p53, Bax loci, etc.) may escape apoptosis, thereby revealing the full mitogenic potential of the E2F4 transcription factor.
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PMID:Nuclear expression of E2F4 induces cell death via multiple pathways in normal human intestinal epithelial crypt cells but not in colon cancer cells. 1765 49

Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3',5'-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence.
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PMID:Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation. 1790 36


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