Journal Article

Changes in <i>O</i><sup>6</sup>-methylguanine-DNA methyltransferase expression during immortalization of cloned human fibroblasts

Linda C. Harris, Mathew A. von Wronski, Carol C. Venable, Joanna S. Remack, Sherie R. Howell and Thomas P. Brent

in Carcinogenesis

Volume 17, issue 2, pages 219-224
Published in print February 1996 | ISSN: 0143-3334
Published online February 1996 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.2.219
Changes in O6-methylguanine-DNA methyltransferase expression during immortalization of cloned human fibroblasts

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Suppressed expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), characterized as the Mer phenotype, occurs only in malignant or transformed cell lines. To investigate the relationship between the transformation process and loss of MGMT expression, we derived 20 cloned lines of IMR90 normal fibroblasts transfected with the plasmid pSV3neo expressing the SV40 large-T antigen. Of the five lines that were grown until crisis phase, four emerged as continuously proliferating immortal lines. Of these, only one retained MGMT, the other three having become Mer. In every case the loss of MGMT coincided with the final phase of immortalization following crisis. Because these were cloned cell lines it is clear that the phenotypic change to Mer is not merely due to selection of a Mer cell from the initial population, but must involve a cellular change in MGMT regulation, but must involve a cellular change in MGMT regulation. It is not clear if increased mutation rate associated with loss of MGMT results in increased frequency of an immortalization event or if an immortalization event, such as telomere disruption, results in MGMT suppression. In addition, we have shown that, consistent with previous observations, both hypermethylation in promoter sequences and hypomethylation of downstream sequences in the body of the gene were closely associated with loss of MGMT expression. These studies also illustrate the utility of these new cloned cell lines for characterizing molecular events associated with transformation and immortalization.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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