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The role of the insulin receptor substrate-1 in the differentiation of rat hippocampal neuronal cells

Oncogene volume 20, pages 4842–4852 (2001)Cite this article

Abstract

H19-7/IGF-IR cells are rat hippocampal cells expressing a human IGF-I receptor, which differentiate to a neuronal phenotype when stimulated by IGF-I at 39°C. H19-7/IGF-IR cells have low levels of expression of insulin receptor substrate-l (IRS-1), a major substrate of the IGF-IR. IGF-I induces serine-phosphorylation and down-regulation of the endogenous IRS-1 upon differentiation of H19-7/IGF-IR cells. The profound influence of IRS-1 on differentiation of H19-7/IGF-IR cells was confirmed by transfecting these cells with a plasmid expressing mouse IRS-1. Over-expression of wild type IRS-1 in H19-7/IGF-IR cells abolishes IGF-I-induced differentiation at 39°C. A mutant of IRS-1 lacking the PTB domain loses the ability to inhibit the differentiation program. H19-7/IGF-IR/IRS-1 cells at 39°C show a stronger and prolonged activation of Akt, when compared to H19-7/IGF-IR cells. The role of Akt in the inhibition of the differentiation program was confirmed by using the inhibitor of Class I PI3 kinases LY29400, which restores IGF-I-induced differentiation of H19-7/IGF-IR/IRS-1 cells. H19-7/IGF-IR/IRS-1 cells show a strong reduction in MAP kinases signaling, which is related to the superactivation of Akt. This was confirmed by expressing in H19-7/IGF-IR cells a constitutively active Akt, which inhibited MAP kinases activation in these cells. These experiments confirm the importance of MAPK in the mechanism of IGF-I-mediated differentiation of H19-7/IGF-IR cells

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Acknowledgements

We thank Dr. Phil Tsichlis for the kind gift of Myr-Akt-HA plasmid J Verdone for skilled technical support, and B Rivera for secretarial assistance. This work was supported by NIH grants AG 16291 and CA 78890 to R Baserga. A Morrione is a recipient of an NIDDK Mentored Career Development Award (KO1 DK 02896-01).

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Author notes

  1. Krzysztof Reiss

    Present address: Temple University, College of Science and Technology, Center for Neurovirology and Cancer Biology, 205 Biology Life Science Building, Room 238, 1900 North 12th Street, Philadelphia, 19122, PA

  2. Barbara Valentinis

    Present address: GenEra S. p.A, Via Olgettina, 58, Milano, 20132, Italy

Authors and Affiliations

  1. Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, Philadelphia, 624, 19107, BLSB, Pennsylvania, PA, USA

    Andrea Morrione, Magali Navarro, Gaetano Romano, Michael Dews, Krzysztof Reiss, Barbara Valentinis, Barbara Belletti & Renato Baserga

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  1. Andrea Morrione
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Correspondence to Renato Baserga.

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Morrione, A., Navarro, M., Romano, G. et al. The role of the insulin receptor substrate-1 in the differentiation of rat hippocampal neuronal cells. Oncogene 20, 4842–4852 (2001). https://doi.org/10.1038/sj.onc.1204649

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