Correlation of thyroid hormone dose-dependent regulation of K-ras protooncogene expression with oncogene activation by 3-methylcholanthrene: loss of thyroidal regulation in the transformed mouse cell.
Previously, it has been demonstrated that thyroid hormone is an important cofactor of the initiation of oncogenesis in vivo and in vitro. In order to determine the mechanism of thyroid hormone modulation of the initiation of carcinogenesis we have addressed the hypothesis that thyroid hormone regulates the expression of the critical protooncogene at the time of exposure to the carcinogen, and that the transcriptional activity of the protooncogene correlates with the ability of a carcinogen to "activate" the oncogene and thus modulate the subsequent transformation event. It has previously been shown that 3-methylcholanthrene transformation of C3H/10T1/2 mouse embryo cells in culture is the result of activation of the k-ras oncogene. We report here that thyroid hormone modulates 3-methylcholanthrene transformation of C3H/10T1/2 cells in a dose-dependent manner that is similar to a thyroid hormone dose-dependent modulation of k-ras-specific RNA levels in these cells. Further, nuclear transcriptional run-on experiments suggest that the thyroidal-induced changes in K-ras RNA levels are a result of a regulation of K-ras transcription. These data support the hypothesis that thyroid hormone modulation of transformation is through regulation of protooncogene expression. It was of further interest to find that 3-methylcholanthrene-transformed C3H/10T1/2 cells have lost the sensitivity to thyroid hormone regulation of "activated" K-ras oncogene transcription and subsequent K-ras-specific RNA levels.
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D009857:Oncogenes; D011519:Proto-Oncogenes; D012334:RNA, Neoplasm / Q000378:metabolism; D013963:Thyroid Hormones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology
D012334:RNA, Neoplasm; D013963:Thyroid Hormones; D014284:Triiodothyronine; D008748:Methylcholanthrene