Signalling pathways involved in antiproliferative effects of IGFBP-3: a review.
Insulin-like growth factor binding protein-3 (IGFBP-3), the major circulating carrier protein for IGFs, is also active in the cellular environment as a potent antiproliferative agent. It appears to function both by cell cycle blockade and the induction of apoptosis. Transfection of p53 negative T47D breast cancer cells to express IGFBP-3 leads to induction of the apoptotic protein bax and an increase in sensitivity to ionising radiation. IGFBP-3 can be transported to the nucleus by an importin beta mediated mechanism, where it has been shown to interact with the retinoid X receptor alpha and possibly other nuclear elements. Expression of oncogenic ras is associated with resistance to exogenous IGFBP-3, the effect being reversible by inhibition of mitogen activated protein (MAP) kinase phosphorylation. IGFBP-3 antiproliferative signalling appears to require an active transforming growth factor beta (TGF-beta) signalling pathway, and IGFBP-3 stimulates phosphorylation of the TGF-beta signalling intermediates Smad2 and Smad3. These recent findings all point to a complex intracellular mode of action of IGFBP-3, which will need to be better understood if anti-cancer treatments are to take advantage of the antiproliferative activity of IGFBP-3.
Baxter
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RC
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065, Australia. robaxter@med.usyd.edu.au
D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000502:physiology
D018972:Insulin-Like Growth Factor Binding Protein 3; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)