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Shc3 affects human high-grade astrocytomas survival

Oncogene volume 24, pages 5198–5206 (2005)Cite this article

Abstract

A selective switch from expression of Shc1 gene to Shc3 occurs with maturation of neuronal precursors into postmitotic neurons. Previous studies showed that in the embryo, Shc1 is maximally expressed in dividing CNS stem cells while it is silenced in mature neurons, where it is replaced by Shc3. Under normal conditions Shc3 is never expressed by glial cells. We now show that in human astrocytomas and glioblastomas, the normal pattern of expression of Shc1/Shc3 is totally subverted, both proteins being present at the same time and in the same cells. Our data indicate that Shc3 is maximally expressed, together with Shc1, in glioblastoma, a highly proliferative tumor with little, if any, indication of neuronal differentiation. In primary cultures of glioblastoma, tumor cells maintain Shc1 expression but downregulate Shc3. Analysis of the phosphorylation status of Shc3 in human glioblastoma tumor samples in vivo indicates that it is tyrosine phosphorylated. Finally, we found that the expression of truncated variants of Shc3 with dominant-negative effects in human high-grade glioma cells that maintain Shc3 expression in vitro leads to a decreased Akt posphorylation and increased apoptosis, thus resulting in impaired survival of the transfected cells. These data suggest that Shc molecules play an important role in glioblastoma cell growth and survival.

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Acknowledgements

We thank Professor G Milanesi for his hospitality and continuous support, Dr M Ferrari (Centro substrati cellulari, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia) for her generous gift of U87MG, U254, U373MG, T98G, CCF-STTG1, SW1088, cell lines and Dr Comicini (Dipartimento di Genetica e Microbiologia Università di Pavia) for his generous gift of the D384 cell line. This work was supported by grants from M.U.R.S.T. (FIRB 2001, Italy; #RBNE01-08) to LM and M.U.R.S.T. (FIRB 2001, Italy; #RBNE01-01) and Associazione Italiana Ricerca sul Cancro (AIRC, Italy) to EC. We thank P delli Santi and I Marini for their excellent technical support.

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Authors and Affiliations

  1. Dipartimento di Chirurgia, Neurochirurgia, Università di Pavia, IRCCS Policlinico S. Matteo, and IGM CNR, P.le Golgi 2, Pavia, 27100, Italy

    Lorenzo Magrassi, Marco Marchionni, Pamela Cassini & Cesare Arienta

  2. Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, Milano, 20133, Italy

    Luciano Conti, Chiara Zuccato & Elena Cattaneo

  3. Department of Neurosurgery, Ospedali Riuniti, Bergamo, Italy

    Andrea Lanterna

  4. Department of Neuroscience and Biomedical Technologies, University Milano-Bicocca, Monza, Italy

    Andrea Lanterna

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  1. Lorenzo Magrassi
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  2. Luciano Conti
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Correspondence to Lorenzo Magrassi.

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Magrassi, L., Conti, L., Lanterna, A. et al. Shc3 affects human high-grade astrocytomas survival. Oncogene 24, 5198–5206 (2005). https://doi.org/10.1038/sj.onc.1208708

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