Nuclear export and mitochondrial and endoplasmic reticulum localization of IGF-binding protein 3 regulate its apoptotic properties.
Tumor suppression by IGF-binding protein 3 (IGFBP3) may occur in an IGF-independent manner, in addition to its role as a regulator of IGF bioavailability. After secretion, IGFBP3 is internalized, rapidly localized to the nucleus, and is later detected in the cytoplasm. We identified a putative nuclear export sequence (NES) in IGFBP3 between amino acids 217 and 228, analogous to the leucine-rich NES sequence of p53 and HIV Rev. Mutation of the NES prevents nucleocytoplasmic shuttling of IGFBP3 and blocks its ability to induce apoptosis. Targeting of IGFBP3 to the mitochondria and endoplasmic reticulum (ER) was confirmed by co-localization with organelle markers using fluorescence confocal microscopy and subcellular fractionation. Mitochondrial targeting was also demonstrated in vivo in IGFBP3-treated prostate cancer xenografts. These results show that IGFBP3 shuttles from the nucleus to the mitochondria and ER, and that nuclear export is essential for its effects on prostate cancer apoptosis.
Division of Pediatric Endocrinology, David Geffen School of Medicine at UCLA, Mattel Children's Hospital, Los Angeles, California 90095, USA.
Vladislava
V
Paharkova-Vatchkova
Kuk-Wha
KW
Lee
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D049790:Nuclear Export Signals; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D018972:Insulin-Like Growth Factor Binding Protein 3; D049790:Nuclear Export Signals