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    Tissue-specific expression and induction of human O6-alkylguanine-DNA alkyltransferase in transgenic mice.

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    Authors
    Rafferty, Joseph A
    Fan, Chun-Yang
    Potter, P M
    Watson, Amanda J
    Cawkwell, L
    O'Connor, Peter J
    Margison, Geoffrey P
    Affiliation
    CRC Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital, Manchester, U.K.
    Issue Date
    1992
    
    Metadata
    Show full item record
    Abstract
    O6-Alkylguanine-DNA alkyltransferase (ATase) activity was determined in crude sonicates of tissues obtained from the F2 offspring of human ATase transgenic founder mice. In certain cases, samples were analyzed both before and after administration of zinc sulfate in the drinking water for 2 wk to upregulate the mouse metallothionein-1 promoter that controls the expression of the transgene. In liver samples obtained by partial hepatectomy, the ATase activities of nontransgenic mice ranged from 63 to 139 fmol/mg total protein (mean of 10 mice, 95.3 +/- 23 fmol/mg), whereas in positive transgenic mice, the range was from 503 to 2119 fmol/mg (mean of 10 mice, 963 +/- 475 fmol/mg). The difference between the mean ATase values for these two groups of mice is highly significant (P less than 0.001). All positive mice expressed ATase and in those examined using the human ATase coding sequence as a probe, isoschizomeric-restriction endonuclease digestion showed no evidence of cytosine methylation in the transgene. After zinc sulfate induction, the ATase levels in residual liver tissue were for the controls 84-191 fmol/mg (mean of 10 mice, 123 +/- 31.5 fmol/mg) and for positive mice 908-3273 fmol/mg (mean of 10 mice, 1960 +/- 724 fmol/mg). Induction thus caused a 1.4- to 3.2-fold increase in ATase activity in the tissues of individual transgenic mice (mean, 1.8-fold; P less than 0.003), with the greatest increase generally occurring in those mice that had the lowest preinduction levels. Hepatic ATase levels were thus increased up to 28 times higher in transgenic mice than in nontransgenic mice. When data from other groups of transgenic and nontransgenic mice (eight of each) was included and analyzed in an independent rather than paired fashion, the mean values for zinc-treated controls and transgenic mice, respectively, were 106 fmol/mg and 1415 fmol/mg, still a highly significant (P less than 0.001) difference. In two mice given a single intraperitoneal dose of cadmium chloride, hepatic ATase increased 2.1- and 4.9-fold, respectively. The effect of partial hepatectomy alone was also considered: for transgenic mice the mean ATase level increased from 453 to 661 fmol/mg protein after 48 h. In other offspring subjected to either unilateral nephrectomy or orchidectomy, induction of ATase activity by zinc sulfate was also seen in kidney (5.7- and 8.4-fold) and testis (1.7- and 3.1-fold), although these observations were made with small numbers of mice.(ABSTRACT TRUNCATED AT 400 WORDS)
    Citation
    Tissue-specific expression and induction of human O6-alkylguanine-DNA alkyltransferase in transgenic mice. 1992, 6 (1):26-31 Mol. Carcinog.
    Journal
    Molecular Carcinogenesis
    URI
    http://hdl.handle.net/10541/108888
    DOI
    10.1002/mc.2940060106
    PubMed ID
    1503642
    Type
    Article
    Language
    en
    ISSN
    0899-1987
    ae974a485f413a2113503eed53cd6c53
    10.1002/mc.2940060106
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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