The polyamines, spermidine and spermine, occur ubiquitously in nature and have been found to be necessary for normal and neoplastic cell growth. Polyamine biosynthesis is an important target for experimental cancer chemotherapy. S-Adenosylmethionine decarboxylase (AdoMetDC) is a key regulated enzyme in the pathway of polyamine biosynthesis and expression of the AdoMetDC gene is controlled by exogenous regulatory signals from growth factors and hormones, as well as by the endogenous levels of the polyamine endproducts of the pathway. Regulation of AdoMetDC expression shows a major component of translational control. In common with a number of other genes involved in the regulation of cell growth, including a number of those encoding oncoproteins and growth factors, the mRNA encoding AdoMetDC contains a small open reading frame in the 5' transcript leader. This open reading frame plays an prominent role in regulating translation of the AdoMetDC mRNA. In order for the open reading frame to exert its regulatory role, it must be translated and the sequence of the encoded peptide is critical. The objective of the proposed studies is to define the mechanism by which upstream open reading frames are involved in regulating translation of AdoMetDC mRNA in particular and transcripts from growth-related genes generally.
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