Shc3 affects human high-grade astrocytomas survival.

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.