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Mol. Cell. Biol. doi:10.1128/MCB.01163-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

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

^* To whom correspondence should be addressed. Email: jxu{at}bcm.tmc.edu.

	Abstract

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 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 C57BL/6J background. However, SRC-3 deficiency affected neither GH nor ALS expression. The low IGF-I in SRC-3^-/- mice was not due to the failure of IGF-I mRNA and protein synthesis, but a consequence of rapid degradation. The rapid IGF-I degradation was associated with a drastically reduced IGFBP-3 levels. Because IGF-I and IGFBP-3 stabilize each other, SRC-3^-/- mice were crossbred with the liver-specific TTR-IGF-I transgenic mice to assess the relationship between reduced IGF-I and IGFBP-3. In SRC-3^-/-/TTR-IGF-I mice, IGF-I level was significantly increased compared with SRC-3^-/- mice, but IGFBP-3 level failed to increase proportionally, indicating that the low IGFBP-3 level is a responsible factor that limits 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 SRC3^-/- mice. Therefore, SRC-3 maintains IGF-I in the circulation through enhancing VDR-regulated IGFBP-3 expression.