Oncogene methylation

J. M. Smith and co-workers, "Methyl Methacrylate Subchronic, Chronic and Oncogenic Inhalation Safety Evaluation Studies," Mbstracts of the Eighteenth Mnnual Meeting of the Society of Toxicology, New Orleans, La., 1979. 

Apart from telomeres, G-quadruplexes are also present in the upstream promoter regions of certain oncogenes. G-quadruplex targeted molecules may interact at these sites as well. In fact, the cationic prophyrin, TMPyP4 and the core modified expanded prophyrin analogue 5,10,15,20-[tetra(N-methyl-3-pyridyl)]-26,28-diselenasapphyrin chloride (Se2SAP) have been found to cause repression of transcriptional activation of c-MYC in cells by G-quadruplex stabilization (Seenisamy et al, 2005). 

Fig. 4. Domain structure of mammalian DNA methyltransferases. (a) The domain structure of the known DNA methyltransferases, depicting the conserved catalytic domain (dark box) and other identified domains. Conserved aminoacid motifs in the catalytic domain are shown in lighter shade of gray. (b) Schematic representation of the reported protein-protein interactions of Dnmtl with a number of regulatory proteins interactions that modulate Dnmtl methyitransferase activity (darker rectangles) or mediate methylation-independent transcriptional repression mechanisms (lighter rectangles). When Dnmtl represses transcription through its enzymatic activity, it has been described to interact with some proteins PCNA [37] and an oncogenic transcription factor PML-RAR [25]. Note that in the case of the PML-RAR transcription factor, histone deacetylase 1 (HDACl) is also bound to the complex. When Dnmtl represses transcription via methylation-independent pathways, it binds to HDACs either directly [34] or indirectly through other proteins the corepressor DMAPl [33], the retinoblastoma protein, and a gene-specific transcription factor [31].

HDACl and binds to methyl-CpG through its SRA domain. Oncogene, 23, 7601-7610. 

Wade, P.A. (2001) Methyl CpG binding proteins coupling chromatin architecture to gene regulation. Oncogene, 20, 3166-3173. 

Christman, J.K. (2002) 5-Azacytidine and 5-aza-2 -deoxycytidine as inhibitors of DNA methylation mechanistic studies and their implications for cancer therapy. Oncogene, 21, 5483-5495. 

Reininghaus W, Koestner A, Klimisch HJ Chroic toxicity and oncogenicity of inhaled methyl acrylate and w-butyl acrylate in Sprague-Dawley rats. Food Chem Toxicol 29 329-339, 1991... 

No exposure-related clinical signs or lesions of systemic toxicity and no oncogenic responses were observed in rats exposed by inhalation at concentrations of 0, 15, 45, or 135ppm 6 hours/day, 5 days/week, for 24 consecutive months." Dose-related changes occurred in the anterior portion of the olfactory epithelium and consisted of atrophy of the neurogenic epithelial cells followed by progressive hyperplasia of the reserve cells and ultimately loss of the upper epithelial cell layer. Opacity and neovascularization of the cornea were also observed in methyl acrylate-exposed animals. 

Lomax LG, Krivanek ND, Erame SR Chronic inhalation toxicity and oncogenicity of methyl methacrylate in rats and hamsters. Food Chem Toxicol 35(3-I) 393-I07, 1997... 

Bertram, J.S. and Heidelberger, C. (1974). Cell cyclic dependency of oncogenic transformation induced by N-methyl-N -nitio-N-nitrosoguanidine in culture, Cancer Res. 34,526. 

Steele, V.E., IVIarchok, A.C., and Nettensheim, P. (1979). Oncogenic transformation in epithelial cell lines derived from tracheal explants exposed in vitro to N-methyl-N-nitro N nitrosoguanine, Cancer Res. 39,3805. 

In female mammalian cells most of the genes on one of the two X-chromosomes are completely inactivated. DNA methylation plays a major role in this process.244 245 A perfect correlation has been observed between 5 -methylation of cytosines in CpG islands and inactivation of X-chromosome genes.246 Methylation may also play a role in recombination and repair.247 Methylation of DNA decreases with increasing age.248 It increases as a result of oncogenic transformation of cells.249 Some other modifications of DNA largely limited to bacteriophages are discussed on p. 234 247/250... 

Bird, M., H. Burleigh-Flayer, J. Chun, and J. Douglas. 1997. Oncogenicity studies of inhaled methyl tertiary butyl ether (MTBE) in CD-I mice and F-344 rats. J. Appl. Toxicol. 17 S45-S55. 

Krynetski E, Evans WE. Drug methylation in cancer therapy lessons from the TPMT polymorphism. Oncogene 2003 22 7403-7413. 

Wozniak RJ, Klimecki WT, Lau SS et al (2007) 5-Aza-2 -deoxycytidine-mediated reductions in G9A histone methyltransferase and histone H3 K9 di-methylation levels are linked to tumor suppressor gene reactivation. Oncogene 26 77-90... 

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