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Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.

ABSTRACT: Insulin-like growth factor-binding protein-3 (IGFBP-3) regulates IGF bioactivity and also independently modulates cell growth and survival. By using a yeast two-hybrid screen to identify IGFBP-3-interacting proteins, we cloned humanin (HN) as an IGFBP-3-binding partner. HN is a 24-aa peptide that has been shown to specifically inhibit neuronal cell death induced by familial Alzheimer's disease mutant genes and amyloid-beta (Abeta). The physical interaction of HN with IGFBP-3 was determined to be of high affinity and specificity and was confirmed by yeast mating, displaceable pull-down experiments with (His)-6-tagged HN, and ligand blot experiments. Co-immunoprecipitation of IGFBP-3 and HN from mouse testes confirmed the interaction in vivo. In cross-linking experiments, HN bound IGFBP-3 but did not compete with IGF-I-IGFBP-3 binding; competitive ligand dot blot experiments revealed the 18-aa heparin-binding domain of IGFBP-3 as the binding site for HN. Alanine scanning determined that F6A-HN mutant does not bind IGFBP-3. HN but not F6A-HN inhibited IGFBP-3-induced apoptosis in human glioblastoma-A172. In contrast, HN did not suppress IGFBP-3 response in SH-SY5Y neuroblastoma and mouse cortical primary neurons. In primary neurons, IGFBP-3 markedly potentiated HN rescue ability from Abeta1-43 toxicity. In summary, we have identified an interaction between the survival peptide HN and IGFBP-3 that is pleiotrophic in nature and is capable of both synergistic and antagonistic interaction. This interaction may prove to be important in neurological disease processes and could provide important targets for drug development.

SUBMITTER: Ikonen M

PROVIDER: S-EPMC240741 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

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Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.

Ikonen Maaria M Liu Bingrong B Hashimoto Yuichi Y Ma Liqun L Lee Kuk-Wha KW Niikura Takako T Nishimoto Ikuo I Cohen Pinchas P

Proceedings of the National Academy of Sciences of the United States of America 20031015 22

Insulin-like growth factor-binding protein-3 (IGFBP-3) regulates IGF bioactivity and also independently modulates cell growth and survival. By using a yeast two-hybrid screen to identify IGFBP-3-interacting proteins, we cloned humanin (HN) as an IGFBP-3-binding partner. HN is a 24-aa peptide that has been shown to specifically inhibit neuronal cell death induced by familial Alzheimer's disease mutant genes and amyloid-beta (Abeta). The physical interaction of HN with IGFBP-3 was determined to be ...[more]

PMID: 14561895

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Project description:Heparin-binding insulin-like growth factor 1 (HB-IGF-1) is a fusion protein of IGF-1 with the HB domain of heparin-binding epidermal growth factor-like growth factor. A single dose of HB-IGF-1 has been shown to bind specifically to cartilage and to promote sustained upregulation of proteoglycan synthesis in cartilage explants. Achieving strong integration between native cartilage and tissue-engineered cartilage remains challenging. We hypothesize that if a growth factor delivered by the tissue engineering scaffold could stimulate enhanced matrix synthesis by both the cells within the scaffold and the adjacent native cartilage, integration could be enhanced. In this work, we investigated methods for adsorbing HB-IGF-1 to self-assembling peptide hydrogels to deliver the growth factor to encapsulated chondrocytes and cartilage explants cultured with growth factor-loaded hydrogels. We tested multiple methods for adsorbing HB-IGF-1 in self-assembling peptide hydrogels, including adsorption prior to peptide assembly, following peptide assembly, and with/without heparan sulfate (HS, a potential linker between peptide molecules and HB-IGF-1). We found that HB-IGF-1 and HS were retained in the peptide for all tested conditions. A subset of these conditions was then studied for their ability to stimulate increased matrix production by gel-encapsulated chondrocytes and by chondrocytes within adjacent native cartilage. Adsorbing HB-IGF-1 or IGF-1 prior to peptide assembly was found to stimulate increased sulfated glycosaminoglycan per DNA and hydroxyproline content of chondrocyte-seeded hydrogels compared with basal controls at day 10. Cartilage explants cultured adjacent to functionalized hydrogels had increased proteoglycan synthesis at day 10 when HB-IGF-1 was adsorbed, but not IGF-1. We conclude that delivery of HB-IGF-1 to focal defects in cartilage using self-assembling peptide hydrogels is a promising technique that could aid cartilage repair via enhanced matrix production and integration with native tissue.

Dataset Information

Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.

Publications

Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.

Similar Datasets

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