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 dominantnegative
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.