Analysis of the cellular uptake and nuclear delivery of insulin‐like growth factor binding protein‐3 in human osteosarcoma cells

  title={Analysis of the cellular uptake and nuclear delivery of insulin‐like growth factor binding protein‐3 in human osteosarcoma cells},
  author={Lucia Mi{\vc}utkov{\'a} and Martin Hermann and Martin Offterdinger and Michael W. Hess and Andrea Matscheski and Haymo Pircher and Christoph Mueck and Hannes L. Ebner and Andreas Laich and Elisa Ferrando-May and Werner Zwerschke and Lukas A. Huber and Pidder Jansen-D{\"u}rr},
  journal={International Journal of Cancer},
Insulin‐like growth factor (IGF) binding protein‐3 (IGFBP‐3) regulates cell proliferation and survival by extracellular interaction and inactivation of the growth factor IGF‐I. Beyond that, IGF‐independent actions mediated by intracellular IGFBP‐3 including nuclear‐IGFBP‐3, have also been described. We here show, using both confocal and electron microscopy and cell fractionation, that the extracellular addition of IGFBP‐3 to living cells results in rapid uptake and nuclear delivery of IGFBP‐3… 
IGF binding protein‐3 mediates stress‐induced apoptosis in non‐transformed mammary epithelial cells
It is shown that IGFBP‐3 plays a role in stress‐induced apoptosis that may require nuclear localization in non‐transformed MEC, and treatment with IGF‐I had no effect on ANS‐induced nuclear localization, but did block ANS' induced apoptosis.
Nuclear actions of insulin-like growth factor binding protein-3.
Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3): Unraveling the Role in Mediating IGF-Independent Effects Within the Cell
The aim of this this review is to summarize the complex roles of IGFBP-3 within the cell, including its mechanisms of cellular uptake and its translocation into the nucleus, various molecules with which it is capable of interacting, and its ability to regulate IGF-independent cell growth, survival and apoptosis.
Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions
  • R. Baxter
  • Biology
    Journal of Cell Communication and Signaling
  • 2013
The ability of IGFBP-3 to modulate the balance between pro-apoptotic and pro-survival sphingolipids by regulating sphingosine kinase 1 and sphingomyelinases may be integral to its role at the crossroads between cell death and survival in response to a variety of stimuli.
IGFBP-3 Induced by Ribotoxic Stress Traffics From the Endoplasmic Reticulum to the Nucleus in Mammary Epithelial Cells
Anisomycin and deoxynivalenol specifically induced nuclear localization of nonsecreted IGFBP-3 via an importin-β‒mediated event, which may play a role in their ability to induce apoptosis in MECs.
The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents
In conclusion, IGFBP-3 co-translocation to the nucleus of breast cancer cells and its formation of a complex with DNA-PKcs and EGFR in response to DNA damage shows its potential involvement in the regulation of DNA repair.
Insulin-Like Growth Factor Binding Protein-3 Binds to Histone 3
It is reported for the first time that IGFBP-3 is a histone 3 (H3) binding protein, which could indicate its yet another cellular role in regulating the chromatin remodeling for gene transcription.
It is shown that IGFBP-3 plays a role in stress-induced apoptosis that may require nuclear localization in non-transformed MEC, and treatment with IGF-I had no effect on ANs-induced nuclear localization, but did block ANS-induced suicides.
IGFBP-3: a cell fate pivot in cancer and disease.
  • Michael A Johnson, S. Firth
  • Biology, Medicine
    Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society
  • 2014


Insulin‐Like Growth Factor‐Binding Protein‐5 Enters Vesicular Structures but Not the Nucleus
Quantification of the time and concentration dependence of uptake by immunoblotting revealed that the process was saturable at IGFBP‐5 concentrations between 1 and 2 μm and partially reversible with 30% remaining in the cell after a 1‐h chase.
Cellular Internalization of Insulin-like Growth Factor Binding Protein-3
Together, these data indicate that the actions of IGFBP-3 are mediated by internalization via distinct endocytic pathways.
Nuclear Import of Insulin-like Growth Factor-binding Protein-3 and -5 Is Mediated by the Importin β Subunit*
The results suggest that the NLSs within the C-terminal domain of IGF BP-3 and IGFBP-5 are required for importin-β-dependent nuclear uptake and probably also accumulation through mediating binding to nuclear components.
Nuclear insulin-like growth factor binding protein-3 induces apoptosis and is targeted to ubiquitin/proteasome-dependent proteolysis.
It is suggested that ubiquitin/proteasome-mediated proteolysis of IGFBP-3 may contribute to down-regulation of apoptosis.
Enhancing the apoptotic potential of insulin-like growth factor-binding protein-3 in prostate cancer by modulation of CK2 phosphorylation.
Multi-isite phosphorylation of IGFBP-3 that both positively and negatively regulate its apoptotic potential is revealed, suggesting reciprocal regulation of cell survival and apoptosis by IGF BP-3 and CK2.
Nuclear localization of insulin-like growth factor binding protein 3 in a lung cancer cell line.
It is demonstrated by immunocytochemistry with IGFBP-3 antibodies that nuclei of a lung cancer cell line distinctly immunostain for IGFbp-3, raising the possibility that nuclear IGF BP-3 is functional and involved in the pathogenesis of lung cancer.
Perspectives in mammalian IGFBP-3 biology: local vs. systemic action.
The purpose of this review is to highlight IGFBP-3 as a novel effector molecule and not just another "binding protein" by discussing its IGF-independent actions on metabolism and cell growth.
Insulin-like Growth Factor-binding Protein (IGFBP)-3 and IGFBP-5 Share a Common Nuclear Transport Pathway in T47D Human Breast Carcinoma Cells*
A variant form of IGFBP-3 with a mutation in the putative nuclear localization sequence was unable to translocate to the nuclei of T47D cells, suggesting that nuclear translocation of IGF BP-3 was dependent on these carboxyl-terminal basic residues.
Direct Functional Interactions between Insulin-like Growth Factor-binding Protein-3 and Retinoid X Receptor-α Regulate Transcriptional Signaling and Apoptosis*
RXR- α-IGFBP-3 interaction leads to modulation of the transcriptional activity of RXR-α and is essential for mediating the effects of IGFBP- 3 on apoptosis.
Regulation of insulin receptor substrate‐1 expression levels by caveolin‐1
Results indicate a novel mechanism for the regulation of IRS‐1 expression levels, an important finding in view of IRS•1 role in cell proliferation and transformation.