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Steroid Receptor Coactivator 3 Maintains Circulating Insulin-Like Growth Factor I (IGF-I) by Controlling IGF-Binding Protein 3 Expression

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas,¹ Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas,² The Joint Endocrine Laboratory of Institute of Health Science and Ruijin Hospital, Shanghai Second Medical University, Shanghai, China,³ National Hormone and Pituitary Program, Harbor-UCLA Medical Center, Torrance, California⁴

Received 28 June 2007/ Returned for modification 30 August 2007/ Accepted 18 December 2007

Steroid receptor coactivator 3 (SRC-3/AIB1/ACTR/NCoA-3) is a transcriptional coactivator for nuclear receptors including vitamin D receptor (VDR). Growth hormone (GH) regulates insulin-like growth factor I (IGF-I) expression, and IGF-I forms complexes with acid-labile subunit (ALS) and IGF-binding protein 3 (IGFBP-3) to maintain its circulating concentration and endocrine function. This study demonstrated that the circulating IGF-I was significantly reduced in SRC-3^–/– mice with the C57BL/6J background. However, SRC-3 deficiency affected neither GH nor ALS expression. The low IGF-I level in SRC-3^–/– mice was not due to the failure of IGF-I mRNA and protein synthesis but was a consequence of rapid degradation. The rapid IGF-I degradation was associated with drastically reduced IGFBP-3 levels. Because IGF-I and IGFBP-3 stabilize each other, SRC-3^–/– mice were crossbred with the liver-specific transthyretin (TTR)-IGF-I transgenic mice to assess the relationship between reduced IGF-I and IGFBP-3. In SRC-3^–/–/TTR-IGF-I mice, the IGF-I level was significantly increased over that in SRC-3^–/– mice, but the IGFBP-3 level failed to increase proportionally, indicating that the low IGFBP-3 level is a responsible factor that limits the IGF-I level in SRC-3^–/– mice. Furthermore, IGFBP-3 mRNA was reduced in SRC-3^–/– mice. The IGFBP-3 promoter activity induced by vitamin D, through VDR, was diminished in SRC-3^–/– cells, suggesting an important role of SRC-3 in VDR-mediated transactivation of the IGFBP-3 gene. In agreement with the role of SRC-3 in VDR function, the expression of several VDR target genes was also reduced in SRC-3^–/– mice. Therefore, SRC-3 maintains IGF-I in the circulation through enhancing VDR-regulated IGFBP-3 expression.

Published ahead of print on 22 January 2008.