Primitive neuroectodermal tumors (PNET) are the most common malignant brain tumor of childhood. Using best available therapy, five-year survival for children with PNET is 60%. Surviving children often suffer, cognitive deficits from the effects of antitumor therapy. A better understanding of the genetic alterations and pathways involved in the development of PNET may lead to new types of therapy that prevent recurrence and avoid cognitive deficits in those that survive. ? ? The GSK-3Beta /Beta-catenin/APC pathway consists of a number of interacting elements important in the development of the central nervous system. The subset of patients with Turcot syndrome that have a germline APC mutation have a dramatically increased frequency of PNET. In addition, we have identified oncogenic mutations in Beta-catenin in sporadic PNET. These Beta-catenin mutations are expected to have the same functional consequence as APC inactivation. The mutations identified in Beta-catenin alter GSK-3Beta phosphorylation sites in the protein. Phosphorylated Beta-catenin is bound by APC and targeted for degradation. Hypophosphorylated Beta-catenin avoids degradation and associates with Tcf to form a transactivator. Genes activated by this complex increase cell turnover. We have shown that 36.4% of PNET have nuclear localization of beta-catenin, a marker for activated Beta catenin/Tcf directed transcription. The hypothesis of this grant suggests that alterations of the GSK-3Beta /Beta catenin/APC pathway resulting in increased Beta-catenin/Tcf directed transcription are involved in the oncogenesis of this subset of PNET. ? ? The specific aims of the proposal are aimed at examination of pathway gene function in PNET. The effect of inhibiting Beta-catenin/Tcf transcription in PNET cell lines will be investigated. Genes that inhibit Beta-catenin/Tcf transcription, that sequester Beta-catenin and prevent association with Tcf or that direct degradation of Beta-catenin will be investigated for inactivation. As phosphorylation of Beta-catenin is critical for protein degradation, control of GSK-3Beta activity in PNET will be investigated.
| Butt, Simon J B; Lebret, James M; Kiehn, Ole (2002) Organization of left-right coordination in the mammalian locomotor network. Brain Res Brain Res Rev 40:107-17 |
