Journal Article

<i>O</i><sup>6</sup>-Methylguanine-DNA methyltransferase activity, <i>p53</i> gene status and BCNU resistance in mouse astrocytes

Catherine L. Nutt, Natasha A. Loktionova, Anthony E. Pegg, Ann F. Chambers and J.gregory Cairncross

in Carcinogenesis

Volume 20, issue 12, pages 2361-2365
Published in print December 1999 | ISSN: 0143-3334
Published online December 1999 | e-ISSN: 1460-2180 | DOI:
O6-Methylguanine-DNA methyltransferase activity, p53 gene status and BCNU resistance in mouse astrocytes

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We observed previously that wild-type p53 rendered neonatal mouse astrocytes resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a gene dose-dependent fashion. This effect of p53 appeared to be unrelated to its cell cycle regulation or apoptotic functions. Because in many cell types O6-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair is an important mechanism of resistance to nitrosoureas, we measured MGMT activity in wild-type, heterozygous and p53 knockout neonatal mouse astrocytes. Wild-type p53 astrocytes had significantly greater MGMT activity than either heterozygous or p53 knockout astrocytes: MGMT activity was ~5-fold greater in wild-type p53 astrocytes than in p53 knockout cells. However, despite successful depletion of MGMT activity in wild-type astrocytes by O6-benzylguanine (BG), resistance to BCNU persisted unchanged. Moreover, we excluded the possibility that continued resistance to BCNU at the concentrations used could be explained by a compensatory induction of MGMT triggered by exposure to either BCNU or BG. Although these studies support a role for p53 regulation of MGMT in neonatal mouse astrocytes, BCNU resistance in wild-type cells appears to be mediated by a non-MGMT mechanism. Nevertheless, regulation of DNA repair by MGMT may be another mechanism by which alterations of the p53 gene promote tumor initiation or progression.

Keywords: +/+, wild-type; +/–, heterozygous; –/–, knockout; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; BG, O6-benzylguanine; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MGMT, O6-methylguanine-DNA methyltransferase; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline.

Journal Article.  4398 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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