REGULATION OF ALS AND ITS ROLE IN THE IGF SYSTEM

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The long term objective is to understand the physiology of the insulin-like growth factor system. The IGF system is essential to normal growth and development. Defects in the various components of the IGF system have been identified in cancer, diabetes and undernutrition. In addition to the classical interaction with receptors, IGF-I and IGF-II the ligands of the IGF system associate with six soluble carrier proteins called insulin-like growth factor binding protein (IGFBP1-6). Postnatally, the functional IGF transporting unit is actually a ternary complex formed by association of IGF with IGFBP-3 and a third protein called acid-labile subunit (ALS). The focus of this application is on ALS because current evidence suggests that ALS determines surum levels of IGF-I and -II and their delivery to target tissue. Growth hormone is a major factor controlling the circulating levels of ALS. The mechanisms underlying this regulation, however, have not been defined. This proposal addresses the nature of growth hormone regulation of ALS and its role in vivo. The specific aims and methods are: 1. To determine themechanism by which growth hormone regulates the abundance of ALS mRNA in the liver of mice. This will be done by comparing in liver the abundance of ALS mRNA and the rate of transcription of the gene under different growth hormone status. 2. To define the cis-elements in the 5' upstream region of the ALS gene that mediate the growth hormone and basal activation of transcription. This will be done by transfecting into liver cells luciferase minigenes driven by the promoter of the ALS gene. 3. To study the fuction of the ALS protein in vivo. This will be done by obtaineng and studying mice in which the ALS protein is absent. These mice iwll be created by the gene knockout approach.