Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.44 (AGT)
 770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein O6-alkylguanine-DNA alkyltransferase (O6-AGT) has been implicated as a major determinant of resistance of diverse tumors to chloroethylnitrosoureas. To evaluate the contribution of O6-AGT to resistance of medulloblastomas to chloroethylnitrosoureas, we assessed the role of O6-AGT in determining (BCNU). Sensitivity to BCNU cytotoxicity, measured as dose dependent survival of soft agar colony forming ability, varied among the lines. Two lines (UW443 and UW228-3) displayed linear survival curves and comparable BCNU sensitivity (D37 ca. 140 microM). The other lines (UW228-2 and UW228-1) had biphasic survival curves indicating that each line was composed of two sub-populations that differed in BCNU sensitivity. The D37 for these sub-populations ranged from 51 microM to 253 microM. The O6-AGT activities of the cell lines, however, did not reflect their varied susceptibilities to BCNU as evidenced by a 9-fold difference in O6-AGT activity between UW443 and UW228-3. Moreover, elimination of O6-AGT activity by the inhibitor O6-benzylguanine did not appreciably increase sensitivity to BCNU compared with the response of other human tumor cells [Dolan et al. Cancer Res. 51:3367-3372, 1991]. Our results demonstrate that O6-AGT is not a major determinant of BCNU sensitivity in the four medulloblastoma lines.
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PMID:O6-alkylguanine DNA-alkyltransferase is not a major determinant of sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea in four medulloblastoma cell lines. 142 17

The cerebellar medulloblastoma (WHO Grade IV) is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Several molecular alterations appear to be involved, including isochromosome 17q and the p53, PTCH, and beta-catenin gene mutations. In this study, 46 sporadic medulloblastomas were screened for the presence of mutations in genes of the Wnt signaling pathway (APC and beta-catenin). Single-strand conformational polymorphism (SSCP) analysis followed by direct DNA sequencing revealed 3 miscoding APC mutations in 2 (4.3%) medulloblastomas. One case contained a GCA-->GTA mutation at codon 1296 (Ala-->Val), and another case had double point mutations at codons 1472 (GTA-->ATA, Val-->Ile) and 1495 (AGT-->GGT, Ser-->Gly). Miscoding beta-catenin mutations were detected in 4 tumors (8.7%). Three of these were located at codon 33 (TCT -->TTT, Ser-->Phe) and another at codon 37 (TCT-->GCT, Ser-->Ala). Adenomatous polyposis coli (APC) gene and beta-catenin mutations were mutually exclusive and occurred in a total of 6 of 46 cases (13%). Although germline APC mutations are a well established cause of familial colon and brain tumors (Turcot syndrome), this study provides the first evidence that APC mutations are also operative in a subset of sporadic medulloblastomas.
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PMID:APC mutations in sporadic medulloblastomas. 1066 72