Brain and liver targeted overexpression of O6-methylguanine DNA methyltransferase in transgenic mice

Christi A. Walter, Jianwei Lu, Mukesh Bhakta, Sankar Mitra, William Dunn, Damon C. Herbert, Frank J. Weaker, Tom Hoog, Paula Garza, Gwen S. Adrian, Nuanthip Kamolvarin

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Abstract

O6Methylguanine DNA methyltransferase (MGMT; EC 2.1.1.63) is an unusual DNA repair protein in that it directly and specifically repairs a premutagenic DNA lesion without involving other proteins. MGMT removes the alkyl group from O6-alkylguanine in DNA in a unique stoichiometric reaction by accepting the alkyl group on a cysteine residue. The intracellular level of MGMT varies among tissues and appears to be inversely correlated to tissue-specific tumorigenesis induced by monofunctional alkylating agents. Because MGMT acts in solo, genetic manipulation of its expression may provide valuable insight into its contribution to cellular resistance to alkylation toxicity and to tumor induction. The human MGMT full length cDNA has been fused with a portion of the human transferrin (TF) 5'-flanking region (TF/MGMT). Transgenic founder mice were produced carrying the TF/MGMT transgene and then bred to establish stable transgenic lines. Human MGMT transcripts were specifically expressed in abundance in transgenic brain and liver tissues. In vitro MGMT assays revealed ∼ 150-fold and ∼25-fold increases in MGMT activity in transgenic brain and liver extracts respectively. Western blot analysis confirmed that human MGMT protein is specifically synthesized in transgenic brain and liver tissues.

Original languageEnglish (US)
Pages (from-to)1537-1543
Number of pages7
JournalCarcinogenesis
Volume14
Issue number8
DOIs
StatePublished - Aug 1 1993

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Walter, C. A., Lu, J., Bhakta, M., Mitra, S., Dunn, W., Herbert, D. C., Weaker, F. J., Hoog, T., Garza, P., Adrian, G. S., & Kamolvarin, N. (1993). Brain and liver targeted overexpression of O6-methylguanine DNA methyltransferase in transgenic mice. Carcinogenesis, 14(8), 1537-1543. https://doi.org/10.1093/carcin/14.8.1537