Shc3 affects human high-grade astrocytomas survival

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.

Distinct role of ShcC docking protein in the differentiation of neuroblastoma

“…Furthermore, the proportion of apoptotic cells in the nude mouse tumors generated from neuroblastoma cells in vivo was remarkably increased by the knockdown of ShcC. In recent study, Magrassi et al (2005) showed that ShcC positively effects on cell survival by PI3K-AKT pathway in glioma cells using dominant negative form of ShcC. Theses data indicate that ShcC has additional function in the protection from some types of apoptosis in addition to the induction of differentiation of cells.…”

Real‐time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12‐q13

“…Overexpression of S100A11 has been linked with the development of lymph node metastases in gastric cancer (Mori et al, 2004), whereas increased expression of JTB has been reported in hepatocellular carcinoma (Wong et al, 2003). High expression of SHC1 has been found in dividing CNS stem cells in the embryo (Conti et al, 2001) and in human astrocytomas and glioblastomas (Magrassi et al, 2005). To our knowledge, this is the first report of additional copies of these genes in intracranial pediatric ependymomas.…”

Lentiviral Vector-Mediated SHC3 Silencing Exacerbates Oxidative Stress Injury in Nigral Dopamine Neurons by Regulating the PI3K-AKT-FoxO Signaling Pathway in Rats with Parkinson’s Disease

“…Interestingly, the stress response factor FoxO3, a member of the FoxO family, was considered neuroprotective in PD by another study [48]. Moreover, SHC3 was found to positively affect neural cell survival through decreased Akt phosphorylation [37]. Therefore, the aforementioned findings demonstrate that the PI3K-AKT-FoxO signaling pathway was downregulated via SHC3 silencing in nigral dopamine neurons in PD rats.…”

“…It was previously revealed that SHC3 overexpression promotes neuronal cell survival and inhibits apoptosis by activating the PI3K-AKT signaling pathway [36]. A previous study showed that expression of p52SHC3, a truncated variant of SHC3, leads to reduced AKT phosphorylation and enhanced apoptosis in vitro [37]. Previous studies have demonstrated that reduced levels of Cyclin D1 were correlated with decreased protein levels and decreased phosphorylation levels of PI3K-AKT and that inhibition of PI3K coordinately reduces Cyclin E protein levels [38,39].…”