Insulin-like growth factor binding protein-1 (IGFBP-1) is a 30 kDa hepatic protein. It is the major short-term modulator of IGF bioavailability and circulating levels of IGFBP-1 are elevated in a variety of clinical disorders where anabolism is impaired, including poorly controlled diabetes mellitus, renal failure, the AIDS wasting syndrome and human aging. Insulin rapidly suppresses hepatic production of IGFBP-1 at the level of gene transcription via insulin response sequences (IRSs) located in the proximal IGFBP-1 promoter. The investigator has reported that signaling, via protein kinase B (PKB) and forehead proteins, plays a critical role in regulating IGFBP-1 gene expression by insulin. Recent studies indicate that mechanisms mediating the effect of insulin on IGFBP-1 promoter activity are evolutionarily conserved suggesting that they are important in mediating effects of related growth factors on cell survival. Hence, IGFBP1 provides an important model for understanding evolutionarily conserved mechanisms mediating effects of insulin-regulated gene expression in the liver, and the effects of related growth factors on other basic cell processes including cell survival. The proposed studies will use recombinant technologies and cell culture models to examine specific mechanisms by which these transcription factors may contribute to the multi-hormonal regulation of IGFBP-1 promoter activity. Studies in cell culture and animal models will determine whether these mechanisms play a critical role in mediating effects of insulin on endogenous gene expression in the liver. Together, these studies will provide new insight into the role that signaling, via PKB and forkhead proteins, plays in mediating effects of insulin on gene expression in the liver, focusing on the regulation of IGFBP-1.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Deng, Xiong; Zhang, Wenwei; O-Sullivan, InSug et al. (2012) FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287:20132-43
Cypess, Aaron M; Zhang, Hongbin; Schulz, Tim J et al. (2011) Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways. Endocrinology 152:3680-9
Ganjam, Goutham Kumar; Dimova, Elitsa Y; Unterman, Terry G et al. (2009) FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol. J Biol Chem 284:30783-97
Carroll, Robert E; Goodlad, Robert A; Poole, Aleksandra J et al. (2009) Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats. Growth Horm IGF Res 19:447-56
McLoughlin, Thomas J; Smith, Sierra M; DeLong, Alissa D et al. (2009) FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner. Am J Physiol Cell Physiol 297:C548-55
Ono, Mitsuru; Chia, Dennis J; Merino-Martinez, Roxana et al. (2007) Signal transducer and activator of transcription (Stat) 5b-mediated inhibition of insulin-like growth factor binding protein-1 gene transcription: a mechanism for repression of gene expression by growth hormone. Mol Endocrinol 21:1443-57
Allen, David L; Unterman, Terry G (2007) Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am J Physiol Cell Physiol 292:C188-99
Park, Youngkyu; Maizels, Evelyn T; Feiger, Zachary J et al. (2005) Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad. J Biol Chem 280:9135-48
Gan, Lixia; Zheng, Wenhua; Chabot, Jean-Guy et al. (2005) Nuclear/cytoplasmic shuttling of the transcription factor FoxO1 is regulated by neurotrophic factors. J Neurochem 93:1209-19
Purple, C R; Untermann, T G; Pichika, R et al. (2002) Fibronectin fragments upregulate insulin-like growth factor binding proteins in chondrocytes. Osteoarthritis Cartilage 10:734-46

Showing the most recent 10 out of 16 publications