Understanding the mechanisms by which hormones regulate specific function in normal and tumor tissues is the central theme of our research efforts. We have described a novel mechanism for regulation of hormone biosynthesis during study of """"""""switching"""""""" events in rat medullary thyroid carcinoma lines (MTCs). A single hormone-encoding gene can generate five to six structurally different mRNAs, in a tissue-specific fashion, as a consequence of alternative RNA processing events. These mRNAs encode discrete proteins productive of entirely different hormones. Thus, in the case of calcitonin gene expression, one mature mRNA produced in thyroidal """"""""C"""""""" cells encodes two component hormones (calcitonin and a new hormone which we refer to as CCP); while a second mRNA, produced in the hypothalamus, encodes a new putative hormone, which we refer to as calcitonin gene-related peptide (CGRP). The generation of alternative RNA and protein products from a single endocrine gene is referred to as """"""""peptide switching."""""""" Several experimental approaches will be utilized to establish whether these switching events result from bona fide RNA processing alterations, or are consequential to altered transcriptional initiation or termination or to altered genomic structure. Experiments designed to demonstrate the production of predicted peptides and to define functions of the new putative hormones will be initiated. The production of CGRP by hypothalamus and its tissue distribution will be confirmed by construction and sequencing of appropriate cDNA clones. Possible hormonal regulation of """"""""peptide switching"""""""" events will be studied in clonal cell lines derived from MTC tumors. Additional studies will explore the possible clinical ramifications of these events in the diagnosis and biology of human cancers, particularly carcinomas of the lung. (C)
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