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PubMed1997

Regulation of FAT/CD36 gene expression: further evidence in support of a role of the protein in fatty acid binding/transport.

Much biochemical evidence has implicated rat adipocyte CD36 (FAT) in membrane binding and transport of long-chain fatty acids (FA). Expression of the mRNA favored tissues with active FA metabolism and was upregulated in vivo with diabetes and with high fat feeding. In culture, CD36 mRNA was a strong marker of preadipocyte differentiation and was modulated by the same factors effective on mRNAs coding for other proteins involved in FA metabolism. In preadipocytes, long-chain FA or 2-bromopalmitate but not short-chain FA strongly induced CD36 mRNA within 8 h to an optimum within 24 h. Removal of the FA resulted in a decay of CD36 mRNA with a half life of about 12 h. In differentiated adipocytes, levels of CD36 mRNA were downregulated by the 3': 5'-cyclic adenosine monophosphate, cAMP, analog, 8-(4-chlorophenylthio) adenosine, 8-CPT, at concentrations of 1-100 microM. The effect, observed within 6 h, was optimal after 18 h and independent of the action of 8-CPT to mobilize FA. Regulation of CD36 expression by factors effective on expression of other proteins implicated in FA metabolism is consistent with its role in membrane FA transport.

Adipocytes↗

PubMed2005

The language of methylation in genomics of eukaryotes.

Background studies have shown that 6-methylaminopurine (m6A) and 5-methylcytosine (m5C), detected in DNA, are products of its post-synthetic modification. At variance with bacterial genomes exhibiting both, eukaryotic genomes essentially carry only m5C in m5CpG doublets. This served to establish that, although a slight extra-S phase asymmetric methylation occurs de novo on 5'-CpC-3'/3'GpG-5', 5'-CpT-3'/3'-GpA-5', and 5'-CpA-3'/3'-GpT-5' dinucleotide pairs, a heavy methylation during S involves Okazaki fragments and thus semiconservatively newly made chains to guarantee genetic maintenance of -CH3 patterns in symmetrically dimethylated 5'-m5CpG-3'/3'-Gpm5C-5' dinucleotide pairs. On the other hand, whilst inverse correlation was observed between bulk DNA methylation, in S, and bulk RNA transcription, in G1 and G2, probes of methylated DNA helped to discover the presence of coding (exon) and uncoding (intron) sequences in the eukaryotic gene. These achievements led to the search for a language that genes regulated by methylation should have in common. Such a deciphering, initially providing restriction minimaps of hypermethylatable promoters and introns vs. hypomethylable exons, became feasible when bisulfite methodology allowed the direct sequencing of m5C. It emerged that, while in lymphocytes, where the transglutaminase gene (hTGc) is inactive, the promoter shows two fully methylated CpG-rich domains at 5 and one fully unmethylated CpG-rich domain at 3' (including the site +1 and a 5'-UTR), in HUVEC cells, where hTGc is active, in the first CpG-rich domain of its promoter four CpGs lack -CH3: a result suggesting new hypotheses on the mechanism of transcription, particularly in connection with radio-induced DNA demethylation.

Base Sequence↗

PubMed2000

[Response of metastatic colorectal cancers to treatment with CPT11 (irinotecan): implications of the mismatched base repair system].

AIMS: The aim of our study was to assess the potential relationships between tumor responsiveness to CPT11, an analogue of camptothecin, which selectively inhibits DNA topoisomerase I, and the microsatellite instability, a feature of tumors with DNA mismatch repair defect. METHODS: We designed a retrospective clinical study including 35 patients with metastatic colorectal cancer treated with CPT11, for which we analyzed the expression of hMLH1 and hMSH2 in the tumor and determined microsatellite status of repeated mononucleotide tracts present in the coding region of RII-TGFB, BAX, hMSH3 and hMSH6 genes. RESULTS: A partial or minor response was observed in 9 patients, disease stabilization in 14 patients and progression in 12 patients. Staining of hMLH1 was undetectable in 2 of the 35 tumors, while only 1 tumor lacked hMSH2 expression. Four of the 31 tumors analyzed displayed intragenic microsatellite instability. We found a good correlation between inactivation of TGFB-RII, BAX or hMSH3 genes and tumor response to CPT-11 (P =0.002). CONCLUSION: Our preliminary data suggest that intragenic microsatellite instability may influence tumor response to CPT-11 in patients with colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed1994

Densely methylated DNA islands in mammalian chromosomal replication origins.

Densely methylated DNA sequence islands, designated DMIs, have been observed in two Chinese hamster cell chromosomal replication origins by using a PCR-based chemical method of detection. One of the origins, oriS14, is located within or adjacent to the coding sequence for ribosomal protein S14 on chromosome 2q, and the other, ori-beta, is approximately 17 kbp downstream of the dhfr (dihydrofolic acid reductase) locus on chromosome 2p. The DMI in oriS14 is 127 bp long, and the DMI in ori-beta is 516 bp long. Both DMIs are bilaterally methylated (i.e., all dCs are modified to 5-methyl dC) only in cells that are replicating their DNA. When cell growth and DNA replication are arrested, methylation of CpA, CpT, and CpC dinucleotides is lost and the sequence islands display only a subset of their originally methylated CpG dinucleotides. Several possible roles for DMI-mediated regulation of mammalian chromosomal origins are considered.

Animals↗

PubMed1996

Cycling probe technology with RNase H attached to an oligonucleotide.

A streptavidin-RNase H gene fusion was constructed by cloning the Thermus thermophilus RNase H coding sequence in the streptavidin expression vector pTSA18F. The gene was expressed in Escherichia coli, and the resulting fusion protein was purified to apparent homogeneity. The fusion protein was shown to have a molecular weight of 128 kDa and to consist of four subunits. Furthermore, heat treatment of the fusion enzyme showed that it was stable as a tetramer at 65 degrees C. The fusion enzyme was shown to have both biotin binding and RNase H catalytic properties. Using cycling probe technology (CPT), the fusion enzyme was compared to the native RNase H with a biotinylated probe at different ratios of probe:enzyme and varying amounts of synthetic target DNA. At a ratio of 1:1, the fusion enzyme was active in CPT, but the native enzyme was not; both enzymes were active at a 1:5000 ratio of probe:enzyme. The fusion enzyme was further tested using biotinylated and non-biotinylated probes and was shown to be active at a 1:1 ratio with the biotinylated probe but not with the non-biotinylated probe. These experiments show that through binding of the streptavidin-RNase H fusion enzyme to the biotinylated probe, the efficiency of the cycling probe reaction is enhanced.

Bacterial Proteins↗

PubMed2004

Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms.

Irinotecan hydrochloride (CPT-11) is a potent anticancer drug that is converted to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), and other metabolites in liver. The disposition and gastrointestinal toxicity of irinotecan exhibit a wide interpatient variability. Here, we examined the contribution of an organic anion-transporting polypeptide, OATP1B1 (OATP-C), which transports a variety of drugs and their metabolites from blood to liver in humans, to the hepatic disposition of irinotecan, SN-38, and its glucuronide conjugate (SN-38G) by using HEK293 cells stably transfected with SLCO1B1*1a (OATP-C*1a) coding wild-type OATP1B1. We further examined the effect of single nucleotide polymorphisms in OATP1B1 by measuring uptake activity in Xenopus oocytes expressing OATP1B1*1a and three common variants. In all cases, transport activity for SN-38 was observed, whereas irinotecan and SN-38G were not transported. Moreover, SN-38 exhibited a significant inhibitory effect on OATP1B1-mediated uptake of [(3)H]estrone-3-sulfate. Among the variants examined, OATP1B1*15 (N130D and V174A; reported allele frequency 10-15%) exhibited decreased transport activities for SN-38 as well as pravastatin, estrone-3-sulfate, and estradiol-17beta-glucuronide. This study is the first to yield evidence that OATP1B1 is involved in the hepatic disposition of SN-38 and that genetic polymorphisms of OATP1B1 may contribute to the known interpatient variability in disposition of irinotecan.

Animals↗

PubMed1986

Regulation of gene expression in rat hepatocytes and hepatoma cells by insulin: quantitation of messenger ribonucleic acid's coding for tyrosine aminotransferase, tryptophan oxygenase, and phosphoenolpyruvate carboxykinase.

The effect of insulin on the abundance of mRNAs coding for tyrosine aminotransferase (TAT; EC 2.6.1.5), tryptophan oxygenase (TO; EC 1.13.1.12), and P-enolpyruvate carboxykinase(GTP) (PEPCK; EC 4.1.1.32) was examined in primary cultures of adult rat hepatocytes and in FTO-2B rat hepatoma cells by Northern blot analysis using RNA probes made from SP6-cDNAs. Insulin (10(-11)-10(-7) M), which has been reported to induce TAT and decrease the activity of TO, did not change the levels of TAT mRNA and TO mRNA in hepatocytes regardless of the presence of other inducers. In the same cells, dexamethasone increased TAT mRNA up to 19-fold and TO mRNA up to 15-fold, and 8pClPhS-cAMP (CPT-cAMP) raised the level of TAT mRNA up to 36-fold. The abundance of TO mRNA was not altered by CPT-cAMP. In contrast to TAT mRNA and TO mRNA, the level of PEPCK mRNA was dramatically decreased by insulin in the same hepatocytes. The sensitivity to this inhibitory effect of insulin was enhanced by dexamethasone and reduced by CPT-cAMP. FTO-2B hepatoma cells, which do not express detectable levels of TO mRNA, showed responses similar to those of hepatocytes, except that insulin caused a moderate reduction in TAT mRNA, but only in the presence of CPT-cAMP. The PEPCK mRNA in FTO-2B cells was suppressed by insulin in a manner closely resembling the effects in hepatocytes in the present study and in H4IIE hepatoma cells previously reported.

Animals↗

PubMed2001

Allele-specific non-CpG methylation of the Nf1 gene during early mouse development.

Recent reports of cytosine methylation occurring at CpA and CpT dinucleotides in murine ES cells as well as in Drosophila have renewed interest in methylation at sites other than CpGs. Our examination of the murine neurofibromatosis type 1 gene by sodium bisulfite genomic sequencing has revealed non-CpG methylation primarily in the oocyte and the maternally derived allele of the 2-cell embryo, with markedly lower levels found in sperm. Non-CpG methylation was not found in later stages of embryo development or in adult tissue. Our results suggest that maternal-specific de novo non-CpG methylation has occurred sometime between ovulation and formation of the 2-cell embryo, while during the same period the paternally derived allele has undergone site-specific active demethylation. Our data demonstrate both stage and parent-of-origin specific changes in methylation patterns within the neurofibromatosis type 1 coding region-involving cytosines located at both CpG and non-CpG dinucleotides.

Adenosine Deaminase↗

PubMed2003

Use of the rpoB gene to determine the specificity of base substitution mutations on the Escherichia coli chromosome.

Mutations in the rpoB gene of Escherichia coli result in resistance to the antibiotic rifampicin (Rif(r)) by altering the beta subunit of RNA polymerase. Previous studies have identified 39 single base substitutions in the rpoB gene that lead to Rif(r) at 37 degrees C and an additional two mutations that result in temperature sensitive cells. We have extended this work and identified an additional 30 single base substitutions that result in the Rif(r) phenotype. With these mutations the rpoB/Rif(r) system now allows the monitoring of 69 base substitutions at 37 degrees at 37 sites (base pairs) distributed among 24 coding positions. Each of the six possible base substitutions is represented by 8-17 mutations. More than 90% of the mutations are within a small enough region of the rpoB gene to allow PCR amplification with a single pair of oligonucleotide primers, followed by sequencing with a single primer, leading to rapid analysis of numerous mutations. The remaining mutations can be monitored using an additional primer pair. To calibrate this system we sequenced over 500 mutations in rpoB occurring spontaneously or generated by different mutagens and mutators with known specificity. These results show that rpoB/Rif(r) is an accurate and easy to employ detection system, and offers the advantage of allowing analysis of mutations occurring on the chromosome rather than on an extrachromosomal element. The mutS, mutT, mutY, M mutators, as well as the mutagenic agents ethyl methanesulfonate (EMS), ultraviolet (UV) irradiation, 2-aminopurine (2AP), 5-azacytidine (5AZ), and cisplatin (CPT) gave results predicted by their characterized specificities. The number of different sequence contexts is sufficient to reveal significant hotspots among the spontaneous mutS, 2-aminopurine, ultraviolet light, 5-azacytidine, and cisplatin mutational spectra. The cisplatin distribution is particularly striking, with 68% of the mutations resulting from an A:T-->T:A transversion at a single site. Because of the conservation of key regions of RNA polymerase among many microorganisms, using the Rif(r)/rpoB system may be a general method for studying mutational processes in microorganisms without well developed genetic systems.

2-Aminopurine↗

PubMed1997

Projecting corporate health plan utilization and charges from annual ICD-9-CM diagnostic rates: a value-added opportunity for pathologists.

OBJECTIVE: To develop an allocation method for corporate health plan resources and expenditures based on annual International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM) diagnostic rate stratification as a surrogate for disease incidence. DESIGN: A data-mining process was applied to a self-insured corporate health plan database. Annual membership rates of Current Procedural Terminology (CPT) procedure utilization and charges between 1990 and 1994 for a cohort of 7216 continuously employed plan members were stratified according to the annual rates of the 19 major ICD-9-CM diagnostic classifications. The stratified annual CPT utilization and charge rates were analyzed by correlation analysis and one-tailed t test. RESULTS: Laboratory and pathology procedure utilization and charge rates were highly correlated with specific rankings of ICD-9-CM diagnostic classifications. The health plan diagnostic rate, laboratory utilization rate, and all charge rates increased significantly during the 5 study years. CONCLUSION: Although all procedure utilization and charge rates in this health plan increased each year, their proportionality consistently was maintained among diagnostically related groups of patients. By restraining global expenditures, managed health plans conflict with historical utilization and charge patterns. Treating ICD-9-CM diagnostic groups as disease management services within a managed care plan allows procedures and expenses to be allocated according to medical necessity in the context of total membership benefits. For pathologists, who recently were mandated by the Health Care Financing Administration and the Office of Inspector General of the Department of Health and Human Services to become stewards of ICD-9-CM coding, this is a unique opportunity to lead an initiative to perfect managed care. The process will require permanent patient numbers, computerized longitudinal patient records, and standardized coded medical terminology.

Adult↗

PubMed2006

DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53MUT cells contributes to apoptosis.

DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53(WT) colorectal carcinoma cells a long term cell cycle arrest and in p53MUT cells a transient arrest followed by apoptosis (Magrini, R., Bhonde, M. R., Hanski, M. L., Notter, M., Scherübl, H., Boland, C. R., Zeitz, M., and Hanski, C. (2002) Int. J. Cancer 101, 23-31; Bhonde, M. R., Hanski, M. L., Notter, M., Gillissen, B. F., Daniel, P. T., Zeitz, M., and Hanski, C. (2006) Oncogene 25, 165-175). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53WT and five p53MUT established colon carcinoma cell lines to identify gene expression alterations associated with apoptosis in p53MUT cells after treatment with SN-38, the irinotecan metabolite. After treatment, 16 mitosis-related genes were found to be expressed at least 2-fold stronger in the apoptosis-executing p53MUT cells than in the cell cycle-arrested p53WT cells by oligonucleotide microarray analysis. One of the genes whose strong post-treatment expression was associated with apoptosis was the mitotic checkpoint kinase hMps1 (human ortholog of the yeast monopolar spindle 1 kinase). hMps1 mRNA and protein expression were suppressed by the treatment-induced and by the exogenous adenovirus-coded p53 protein. The direct suppression of hMps1 on RNA level or inhibition of its activity by a dominant-negative hMps1 partly suppressed apoptosis. Together, these data indicate that the high expression of mitotic genes in p53MUT cells after SN-38 treatment contributes to DNA damage-induced apoptosis, whereas their suppression in p53WT cells acts as a safeguard mechanism preventing mitosis initiation and the subsequent apoptosis. hMps1 kinase is one of the mitotic checkpoint proteins whose expression after DNA damage in p53MUT cells activates the checkpoint and contributes to apoptosis.

Antineoplastic Agents, Phytogenic↗

PubMed1988

The gamma-crystallin gene families: sequence and evolutionary patterns.

The gamma-crystallin proteins consist of two topologically equivalent domains, each built up out of two similar motifs. They are encoded by a gene family, which already contained five members before the divergence of rodents and primates. A further gene duplication took place in each lineage. To analyze the pattern of evolution within this gene family, the coding sequences of six human genes, six rat genes, and four mouse genes were compared. Between species, a uniform rate of evolution of all regions of the protein is seen. The ratio of synonymous to nonsynonymous substitution in the human/rat or human/mouse comparison is much lower than the ratio when rat and mouse are compared indicating that the gamma-crystallin proteins are better conserved in the rodent lineage. Within species, the regions encoding the two external motifs I and III of the protein show a greater extent of nonsynonymous substitution than the regions encoding the two internal protein motifs II and IV. The low extent of synonymous substitution between the second exons (encoding motifs I and II) of the rat gamma-crystallin genes suggests the frequent occurrence of gene conversion. In contrast, a high extent of synonymous substitution is found in exon 3 (encoding motifs III and IV) of the rat genes. The same phenomenon is seen within the human gene family. The frequencies of occurrence of the various dinucleotides deviate less from those predicted from the frequencies of occurrence of each individual nucleotide in the second exons than in the third exons. The sequences of the third exons are significantly depleted in CpG, ApA, and GpT and enriched in CpT and GpA.

Animals↗

PubMed1987

Isolation and characterization of a yeast mutant defective in cholinephosphotransferase.

A yeast mutant defective in cholinephosphotransferase (cpt) was isolated as a revertant from a choline-sensitive mutant, which exhibited lowered phosphatidylinositol synthesis. A block at the cholinephosphotransferase step in the mutant was indicated by the enzyme defect and the accumulation of CDP-choline in the cells with a decrease in phosphatidylcholine synthesis. The defect was due to a single recessive mutation in a nuclear gene. The residual activity in the mutant showed an increased apparent Km for CDP-choline and an altered sensitivity to Tween 20. Thus the structural gene may be affected in the mutant. The occurrence of an intact ethanolaminephosphotransferase in the mutant indicates the distinctness of the genes encoding cholinephosphotransferase and ethanolaminephosphotransferase in yeast. The present selection method was also effective for isolating mutants defective in the other steps of the CDP-choline pathway and choline transport.

Choline↗

PubMed2003

Antitumor triptycene bisquinones: a novel synthetic class of dual inhibitors of DNA topoisomerase I and II activities.

Synthetic triptycene analogs (TT code number) mimic the antitumor effects of daunorubicin in the nanomolar range in vitro, but have the advantage of blocking nucleoside transport and retaining their efficacy in multidrug-resistant (MDR) tumor cells. Since TT bisquinones induce poly(ADP-ribose) polymerase-1 cleavage at 6 h and internucleosomal DNA fragmentation at 24 h, which are, respectively, early and late markers of apoptosis, these lead antitumor drugs were tested for their ability to trigger the DNA topoisomerase (Topo) inhibitions responsible for the initial and massive high-molecular-weight cleavage of DNA required for tumor cells to commit apoptosis. Interestingly, antitumor TTs have the unusual ability to inhibit, in a concentration-dependent manner, the relaxation of supercoiled plasmid DNA catalyzed by both purified human Topo I and II enzymes. However, if there is a relationship between the ability of TT analogs to inhibit Topo activities and their quinone functionality and cytotoxicity, it is far from perfect, suggesting that other molecular targets may be involved in the mechanism of action of these antitumor drugs. Moreover, one of the most cytotoxic TT bisquinone, 6-bromo-7-methoxy- or 7-bromo-6-methoxy-2-N-methylamino-1 H,4 H,5 H,8H-9,10-dihydro-9,10-[1',2']benzenoanthracene-1,4,5,8-tetraone (TT24), inhibits Topo II activity more effectively than amsacrine (m-AMSA) and matches the Topo I inhibitory effect of camptothecin (CPT). The dual inhibitory activity of TT24 is substantiated by the findings that TT24 mimics the action of m-AMSA in the Topo II assay, where the Topo I inhibitor CPT is ineffective, and also mimics the action of CPT in the Topo I assay, where the Topo II inhibitor etoposide is ineffective. Because of their ability to target nucleoside transport and topoisomerase activities, synthetic TT bisquinones might represent a novel class of bifunctional drugs valuable to develop new means of polychemotherapy and circumvent MDR.

Animals↗

PubMed2004

Agonist-induced internalization of leukotriene B(4) receptor 1 requires G-protein-coupled receptor kinase 2 but not arrestins.

The leukotriene B(4) (LTB(4)) receptor (BLT1) becomes desensitized upon repeated agonist stimulation. Little is known, however, about BLT1 internalization, which follows desensitization in most G-protein-coupled receptors (GPCR). In the current study, transiently expressed BLT1 readily internalized, after LTB(4) stimulation, in RBL-2H3 cells that express high levels of endogenous GPCR kinase 2 (GRK2) but did not in COS-7 or human embryonic kidney (HEK) 293 cells, which do not overexpress GRK. The internalization of BLT1 could be blocked in RBL-2H3 cells by coexpressing dominant-negative (DN) GRK2 K220R and could be promoted in HEK293 cells by coexpressing wild-type (WT) GRK2. Coexpression of WT or DN nonvisual arrestins had no effect on BLT1 internalization. Moreover, upon stimulation with LTB(4), BLT1 did not induce arrestin-green fluorescence protein redistribution in either cell type, even in the presence of overexpressed GRK2. Coimmunoprecipitation experiments confirmed that BLT1 could associate with GRK2 but not with arrestins. A C-tail-truncated mutant of BLT1 lost the capacity to internalize and associate with GRK2 upon exposure to LTB(4), suggesting that the C-tail was required for receptor internalization and association with GRK2. Taken together, our results indicate that the C terminus of BLT1 plays a pivotal role in receptor internalization and GRK2 association. Moreover, ligand-induced BLT1 internalization is dependent on GRK2 but independent of arrestins. This may allow differential, cell-type-specific signaling in response to LTB(4), depending on GRK expression levels.

Animals↗