Regulation and role of the acid-labile subunit of the 150-kilodalton insulin-like growth factor complex in the mouse

After birth, the acid-labile subunit (ALS) associates in the circulation wi th insulin-like growth factor (IGF)-I or -II and with IGF binding protein-3 (IGFBP-3) to form a 150-kilodalton complex. This association leads to the retention of IGFs in the vascular system and promotes their endocrine actio ns. ALS is synthesized almost exclusively in liver, and both hepatic ALS mR NA and circulating levels are increased by growth hormone (GH). Three major areas of study were pursued to better understand the regulation of ALS syn thesis and its role in the circulating IGF system. First, the mouse ALS gen e was isolated and shown to be organized into two exons and a single intron on chromosome 17. Second, using transient transfection studies in the rat H4-II-E hepatoma cell line and primary rat hepatocytes, the region of the m ouse promoter that is responsive to GH was mapped to a nine-base pair cis-e lement resembling a gamma-interferon-activated sequence. The activation of the mouse ALS gene by GH is mediated by the binding of STAT5 isoforms to th is sequence. Finally, an ALS knockout model was created by inactivating the ALS gene in mouse embryonic stem cells. Mice that are homozygous for the m utation grow at a slower rate after birth. This growth depression is associ ated with large decreases in the plasma concentrations of both IGF-I and IG FBP-3, indicating the critical role of ALS in the regulation of circulating levels of these proteins. Studies of this model will lead to a better unde rstanding of the circulating IGF system.