Chemical genetic identification of the IGF-linked pathway that is mediated by STAT6 and MFP2.

Abstract

Insulin-like growth factor 2 (IGF2) is a potent mitogen whose deregulation plays a role in developing liver, breast, and prostate cancers. Here, we take a small-molecule approach to investigate molecular pathways that modulate IGF2 signaling, by using chromeceptin, a synthetic molecule that selectively impairs the viability and growth of IGF2-overexpressing hepatocellular carcinoma cells. Affinity purification revealed that chromeceptin binds to multifunctional protein 2 (MFP-2), a seemingly multifunctional enzyme implicated in peroxisomal beta-oxidation. The small molecule-protein interaction stimulates the expression of IGF binding protein 1 (IGFBP-1) and suppressor of cytokine signaling-3 (SOCS-3), two cellular attenuators of the IGF signals, through activation of signal transducers and activators of transcription 6 (STAT6). The results underline the importance of STATs in IGF/insulin regulation, and they implicate a new pathway for STAT6 activation that is amenable to small-molecule intervention.

• Authors: Yongmun Choi, Hiroki Shimogawa, Koji Murakami, Latha Ramdas, Wei Zhang, Jun Qin, Motonari Uesugi
• Journal: Chemistry & biology (Chem Biol) Vol. 13 Issue 3 Pg. 241-9 (Mar 2006) ISSN: 1074-5521 [Print] United States
• PMID: 16638529 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Insulin-Like Growth Factor Binding Protein 1
• Multienzyme Complexes
• STAT6 Transcription Factor
• Suppressor of Cytokine Signaling Proteins
• Insulin-Like Growth Factor II
• 17-Hydroxysteroid Dehydrogenases
• Hsd17b4 protein, mouse
• Peroxisomal Multifunctional Protein-2
• Enoyl-CoA Hydratase

Topics

• 17-Hydroxysteroid Dehydrogenases (pharmacology)
• Animals
• Enoyl-CoA Hydratase (pharmacology)
• Gene Expression Regulation (drug effects)
• Insulin-Like Growth Factor Binding Protein 1 (metabolism)
• Insulin-Like Growth Factor II (genetics, metabolism)
• Liver Neoplasms (pathology)
• Mice
• Molecular Sequence Data
• Multienzyme Complexes (pharmacology)
• Oxidation-Reduction
• Peroxisomal Multifunctional Protein-2
• Peroxisomes (metabolism)
• STAT6 Transcription Factor (pharmacology)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling Proteins (metabolism)