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Methyltransferase Inhibitor (methyltransferase + inhibitor)
Selected AbstractsGenetic Selection of Cyclic Peptide Dam Methyltransferase InhibitorsCHEMBIOCHEM, Issue 2 2008Todd A. Naumann Dr. Let's go round. We report the development of a transposition based genetic selection methodology used to uncover three cyclic peptide inhibitors of the E. coli methyltransferase. The activity of the selected cyclic peptides was confirmed in vivo and in vitro. The IC50 of the most active cyclic peptide (SGWYVRNM, shown in the figure) was comparable to that of the known methyltransferase inhibitor, sinefungin. [source] Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer developmentGENES, CHROMOSOMES AND CANCER, Issue 6 2008Kim Loh Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways. © 2008 Wiley-Liss, Inc. [source] Identification of differentially methylated CpG islands in prostate cancerINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004Yasushi Yamada Abstract Epigenetic change such as DNA methylation is one important mechanism for regulating gene expression as genetic change, such as mutation or loss of heterozygosity. Methylation of cancer-related genes has been shown to play an important role in carcinogenesis and tumor progression. Using methylated CpG island amplification (MCA)/representational difference analysis (RDA), we identified four CpG islands in neurotrophin tyrosine kinase receptor type 2 (NTRK2), Protocadherine Flamingo1 and MFPC (Methylated Fragments in Prostate Cancer) 7 and 8. Bisulfite sequencing revealed that 2 regions of NTRK2 as well as MFPC7 and MFPC8 were aberrantly methylated in prostate cancer cell lines, and COBRA showed that 48 (76.24%), 37 (58.7%) and 14 (22.2%) of 63 prostate cancer tissues were methylated, respectively, for these sites. On the other hand, none of 13 benign prostate samples were methylated, except for 1 (7.7%) with NTRK2. For NTRK2, mRNA expression was negative in prostate cancer cell lines (LNCaP and DU145) but was recovered on a methyltransferase inhibitor (5-Aza-CdR) treatment. The role of NTRK2 within NTRK remains unclear. Our results suggest that these 3 hypermethylated DNA fragments also may be markers of prostate cancer detection. © 2004 Wiley-Liss, Inc. [source] Interferon-inducible protein IFIX, inhibits cell invasion by upregulating the metastasis suppressor maspin,MOLECULAR CARCINOGENESIS, Issue 10 2008Hirohito Yamaguchi Abstract IFIX,, a member of the interferon-inducible HIN-200 family, has been identified as a putative tumor suppressor. However, the molecular mechanisms underlying IFIX,-mediated tumor suppression are poorly understood. In the present study, we demonstrated that the metastasis suppressor maspin acts as the downstream target of IFIX,. IFIX, suppressed the invasion activity of MDA-MB-468 breast cancer cells, and its inhibitory effect was reversed by the knockdown of maspin. Both Maspin mRNA and protein were upregulated by IFIX,. Histone deacetylase (HDAC) inhibitors, but not DNA methyltransferase inhibitor upregulated maspin, and HDAC1 inhibited the transactivation of maspin promoter. Although the HDAC1 protein was downregulated in IFIX,-expressing cells, IFIX, did not affect HDAC1 mRNA levels. Conversely, a proteasome inhibitor restored the level of HDAC1 protein in IFIX,-expressing cells, and the polyubiqutination of HDAC1 was promoted by IFIX,, suggesting that HDAC1 is regulated by IFIX, through a ubiquitin-proteasome pathway. Together, these data provide novel insights into the tumor-suppressive function of IFIX,. © 2008 Wiley-Liss, Inc. [source] Maternal chromatin remodeling during maturation and after fertilization in mouse oocytesMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 2 2004Marcella Spinaci Abstract Immunofluorescence staining with antibodies against acetylated histone H4 and 5-methylcytosine was carried out to investigate female chromatin remodeling throughout oocyte maturation and chromatin rearrangement involving both male and female genomes after fertilization. Oocyte cytoplasm remodels female chromatin in preparation of the fertilizing event and the subsequent chromatin rearrangement. Histone H4 are in fact progressively deacetylated whereas demethylating enzymes do not seem to be active over this period. The acetylase/deacetylase balance seems to be cell cycle dependent as female chromatin is deacetylated during maturation and reacetylated at telophase II stage both after fertilization and activation. On the contrary, DNA demethylation seems to be strictly selective. It is in fact confined to the remodeling of paternal genome after fertilization of mature oocytes as the ooplasm is not effective in demethylating either paternal chromatin in germinal vesicle breakdown (GVBD) fertilized oocytes or maternal genome of partenogenetically activated oocytes. Surprisingly, we induced maternal chromatin demethylation after fertilization by treating oocytes with a combination of a methyltransferase inhibitor, 5-azacytidine (5-AzaC), and a reversible and specific inhibitor of histone deacetylase, trichostatin A (TSA). This treatment likely induces a hyperacetylation of histones (thus favoring the access to demethylating enzymes by opening female chromatin structure) associated with a block of reparative methylation by inhibiting methytransferases. This manipulation of chromatin remodeling may have applications regarding the biological significance of aberrant DNA methylation. Mol. Reprod. Dev. 69: 215,221, 2004. © 2004 Wiley-Liss, Inc. [source] Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve MPTP-treated common marmosets: Effect of dose, frequency of administration, and brain exposureMOVEMENT DISORDERS, Issue 5 2003Lance A. Smith MSc Abstract Levodopa (L -dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L -dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L -dopa with the peripheral catechol- O -methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0,7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L -dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L -dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L -dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L -dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L -dopa alone, but with no obvious change in duration of L -dopa's effect. However, combining entacapone with L -dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L -dopa alone. Importantly, increasing pulsatile exposure of brain to L -dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society [source] Genetic Selection of Cyclic Peptide Dam Methyltransferase InhibitorsCHEMBIOCHEM, Issue 2 2008Todd A. Naumann Dr. Let's go round. We report the development of a transposition based genetic selection methodology used to uncover three cyclic peptide inhibitors of the E. coli methyltransferase. The activity of the selected cyclic peptides was confirmed in vivo and in vitro. The IC50 of the most active cyclic peptide (SGWYVRNM, shown in the figure) was comparable to that of the known methyltransferase inhibitor, sinefungin. [source] | ||||||||||