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21. P-Postlabelling method for the detection of 7-alkylguanine adducts formed by the reaction of different 1,2-alkyl epoxides with DNA.

Author

Kumar, Rajiv, Staffas, Joakim, Försti, Asta, and Hemminki, Kari

Abstract

A P-postlabelling method is reported for the detection of 7-alkylguanines, the major adducts formed by the reaction of 1,2-alkylepoxides with DNA. Calf thymus DNA was reacted with different epoxides (ethylene oxide through octylene oxide) and digested with micrococcal nuclease and spleen phosphodiesterase to 3'-nucleotides. The adduct enrichment was carried out by an ion-exchange method and adducts were labelled with [γ-P]ATP in a T4-polynucleotide kinase-mediated reaction. The labelled adducts, prior to resolution by two-dimensional TLC, were treated with nuclease P1. The recoveries of adducts formed by different epoxides ranged from 3 to 10%, tending to increase with the increase in the chain length of the substitutions. The P-postlabelled adducts were also analysed by HPLC coupled with a radioisotope detector. This method has been applied for the detection of 7-alkylguanine adducts in rats exposed to different alkenes. The method has potential for use in measuring human exposure to alkenes or their corresponding epoxides as well as the endogenously formed 7-alkylguanine adducts. [ABSTRACT FROM PUBLISHER]

Published
1995

22. Analysis of UV-induced DNA photoproducts by P-postlabelling.

Author

Bykov, Vladimir J., Kumar, Rajiv, Försti, Asta, and Hemminki, Kari

Abstract

UV-Induced cyclobutane dimers and 6–4 photoproducts, containing an unmodilled nucleotide at the 5'-posltion were released from DNA by means of digestion with DNase I, snake venom phosphodlesterase and prostatic acid phos phatase. The enzymes were deactivated by proteinase K followed by ethanol precipitation. The products were phos phorylated by polynucleotide kinase and [γ-P]ATP. The TLC system used for the analysis enables separation of the different photoproducts and detection at a fmol level. T4 endonuclease treatment was applied to confirm the positions of cyclobutane dimers. [ABSTRACT FROM PUBLISHER]

Published
1995

23. Effect of common <it>B-RAF</it> and <it>N-RAS</it> mutations on global gene expression in melanoma cell lines

Author

Bloethner, Sandra, Chen, Bowang, Hemminki, Kari, Müller-Berghaus, Jan, Ugurel, Selma, Schadendorf, Dirk, and Kumar, Rajiv

Abstract

We studied global gene expression in three melanoma cell lines with the most common and potent V600E mutation in the B-RAF gene—four cell lines with a common Q61R mutation in the N-RAS gene and three cell lines with no mutations using human HG-U133A 2.0 micro-arrays with 22 277 transcripts. Data analysis using stringent criteria revealed several upregulated and downregulated genes in cell lines with B-RAF and N-RAS mutations compared with cell lines without mutations. We found 29 genes specifically upregulated and 32 genes downregulated in cell lines with B-RAF mutations, whereas 70 genes were upregulated and 39 downregulated in cell lines with N-RAS mutations; 11 genes showed overlapping upregulation and 45 downregulation. The micro-array data for nine selected genes were validated by the real-time PCR technique. Expression of a large number of genes, that encode members or regulators of the RAS/RAF/MEK/ERK pathways or are involved in metastasis or invasion, was affected in cell lines with mutations in B-RAF and N-RAS. Upregulated genes in cell lines with mutations included dual-specificity phosphatase 6 (DUSP6), sprouty 2 (SPRY2), v-akt murine thymoma viral oncogene homolog 3 (AKT3) and matrix metalloproteinase 14 (MMP14); downregulated genes included interleukin 18 (IL18), Krüppel-like factor 5 (KLF5) and inhibitor of DNA binding 2 (ID2). Our results, though carried on cell lines, provide a novel insight into the effect of mutations in the B-RAF and N-RAS genes on global gene expression in melanoma and highlight the complexity of mechanisms involved in tumour initiation and maintenance.

Published
2005
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