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Home > Neurosurgery Research > BTRC > Pieper Laboratory  
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Pieper Laboratory
Principal Investigator: Russell O. Pieper PhD

Current Research Projects

Mechanisms of TRAIL resistance in Gliomas
Principal Investigator: Russell O. Pieper PhD

TRAIL is a pro-apoptotic peptide which, when provided exogenously or by activated NK cells, binds TRAIL receptors and induces a tumor-selective cell death. Although many GBM are susceptible to TRAIL-induced cell death, resistance is common, and contributes to the failure of therapies that rely on TRAIL-based killing. We have found that the same lesions that contribute to GBM formation (PTEN loss and Akt activation) also contribute to TRAIL resistance by decreasing the ubiquitination and destruction of the FLIPs protein. The regulation of the ubiquitination process by PTEN is completely undescribed, and in our attempt to unravel how PTEN regulates ubiquitination, FLIPs stability, and TRAIL sensitivity, we have identified two involved proteins; an E3 ubiquitin ligase called AIP4, and a ubiquitin-removing enzyme called USP8. We believe that these two proteins are linked in a PTEN-regulated ubiquitin switch that controls FLIPs stability and in turn TRAIL sensitivity in GBM. Our study of this ubiquitin switch is therefore likely to identify proteins that serve as markers of TRAIL sensitivity in GBM, and to identify new targets, the inhibition of which can sensitize GBM to TRAIL -induced cell death.
 
p38, G2 Arrest, and Temozolomide Resistance in Gliomas
Principal Investigator: Russell O. Pieper PhD

Temozolomide (TMZ) is a chemotherapeutic methylating agent important in the treatment of gliomas. The sensitivity/resistance of gliomas to TMZ is well known to be influenced by the extent of TMZ-induced DNA damage and by the ability of the tumor to repair this damage. The sensitivity/resistance of gliomas to TMZ is also, however, influenced by the G2 cell cycle checkpoint, activation of which can dissociate TMZ-induced DNA damage from TMZ-induced cytotoxicity. The TMZ-induced G2 checkpoint is controlled in part by the Chk1 pathway, activation of which leads to phosphorylation of the Cdc2/cyclin B complex, G2 arrest, and protection from TMZ toxicity. We recently uncovered evidence that a second independent pathway involving the p38 stress kinases may also control TMZ-induced G2 arrest and, in turn, TMZ sensitivity/resistance. Despite its potential importance in controlling TMZ sensitivity/resistance, the activation and consequences of activation of the p38 pathway, as well as its interaction with the Chk1 pathway and potential for therapeutic manipulation remain undefined. In this project we are investigating the means by which the p38 pathway is activated following TMZ-induced DNA damage, how activation of the p38 pathway leads to G2 arrest, how the p38 pathway interacts with the Chk1 pathway, and the consequences of inhibition of the p38 pathway to TMZ sensitivity/resistance. The results of these studies are expected to lead to a better understanding of the TMZ-induced G2 checkpoint, and to identification of ways in which the TMZ-induced G2 checkpoint, and hence TMZ resistance, can be selectively reversed in gliomas.

 
UCSF UCSF Medical Center UCSF School of Medicine
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