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Ret Gene Silencing Is Associated with Raf-1-induced Medullary Thyroid Carcinoma Cell Differentiation¹

Program in Human Genetics and Molecular Biology [E. B. C., S. B. B.] and The Oncology Center [S. B. B., B. D. N.], Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, and DNAX Research Institute for Molecular and Cellular Biology, Palo Alto, California 94304 [M. M.]

Mutations in the ret proto-oncogene constitute the germ line defect in patients with inherited forms of medullary thyroid carcinoma (MTC) and are also present in tumor DNA from a subset of patients with sporadic forms of MTC. We now show that the TT cell line of human MTC can be induced within 48 h to resemble mature C cell differentiation by activation of the raf-1 signal transduction pathway. Within this time period, expression of both the mutant and wild-type ret gene alleles, present in these cells, are silenced at the mRNA and protein levels. This definition of a signal transduction pathway that can regulate ret gene expression, and of the position of ret gene expression in endocrine differentiation, should help clarify the precise role of this gene in normal neuroendocrine development and in the formation of MTC.

¹ This work was supported in part by American Cancer Society Grants DB-43 (S. B. B.) and CN-76829 (B. D. N.) and National Cancer Institute Grant R01-CA47480 (B. D. N.). E. B. C. is a student in the predoctoral training program in Human Genetics (supported by NIH Training Grant 2T32GM07814). The Johns Hopkins Oncology Center Electron Microscopy Resource is supported by National Cancer Institute Grant 5P30CA0697330.

² To whom requests for reprints should be addressed, at Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231.

Received 2/ 6/95. Accepted 4/ 5/95.

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