Abstract
Insulin-like growth factor-binding protein-3 (IGFBP-3) induces apoptosis by its ability to bind insulin-like growth factors (IGFs) as well as its IGF-independent effects involving binding to other molecules including the retinoid X receptor-alpha (RXRalpha). Here we describe that in response to IGFBP-3, the RXRalpha binding partner nuclear receptor Nur77 rapidly undergoes translocation from the nucleus to the mitochondria, initiating an apoptotic cascade resulting in caspase activation within 6 h. This translocation is a type 1 IGF receptor-signaling independent event as IGFBP-3 induces Nur77 translocation in R-cells. IGFBP-3 and Nur77 are additive in inducing apoptosis. GFP-Nur77 transfection into RXRalpha wild-type and knock-out mouse embryonic fibroblasts and subsequent treatment with IGFBP-3 show that RXRalpha is required for IGFBP-3-induced Nur77 translocation and apoptosis. Addition of IGFBP-3 to 22RV1 cell lysates enhanced the ability of GST-RXRalpha to "pull down" Nur77, and overexpression of IGFBP-3 enhanced the accumulation of mitochondrial RXRalpha. This unique nongenotropic nuclear pathway supports an emerging role for IGFBP-3 as a novel, multicompartmental signaling molecule involved in induction of apoptosis in malignant cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Apoptosis*
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Blotting, Western
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Caspases / metabolism
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Cell Nucleus / metabolism*
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Cells, Cultured
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Cytoplasm / metabolism
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DNA-Binding Proteins / metabolism*
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Densitometry
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Dimerization
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Enzyme Activation
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Enzyme-Linked Immunosorbent Assay
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Fibroblasts / metabolism
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Fluorescent Antibody Technique, Indirect
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Glutathione Transferase / metabolism
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Insulin-Like Growth Factor Binding Protein 3 / metabolism
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Insulin-Like Growth Factor Binding Protein 3 / physiology*
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Mice
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Microscopy, Fluorescence
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Mitochondria / metabolism*
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Mutagenesis, Site-Directed
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Protein Transport
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Steroid / metabolism*
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Retinoid X Receptor alpha / metabolism*
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Signal Transduction
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Somatomedins / metabolism*
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Time Factors
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transfection
Substances
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DNA-Binding Proteins
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Insulin-Like Growth Factor Binding Protein 3
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Nr4a1 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Retinoid X Receptor alpha
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Somatomedins
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Transcription Factors
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Glutathione Transferase
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Caspases