Molecular Characterization of Bcl2L12 and its in vivo Role in the Genesis of Glioblastoma

• Applicant: Dr. Alexander Stegh
• Subject Area: Cell Biology
• Term: from 2002 to 2006
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5391604

Glioblastomas (GBM) are aggressive, highly invasive and neurologically destructive brain tumors considered to be among the deadliest of human cancers. In a search to identify novel genes involved in the genesis of GBM, a novel Bcl-2 family member, Bcl2L12 (for Bcl-2 like 12), was found as a potential glioma-genic oncogene that suppresses apoptosis by blocking cysteinyl aspartases (caspases), and promotes growth partially by increasing MAPK activity. In order to comprehensively characterize these activities of Bcl2L12 in vitro and in situ, and to assess its oncogenic potential to promote gliomagenesis in vivo, I propose the following Specific Aims: Specific Aim 1. Molecular characterization of the anti-apoptotic activity of Bcl2L12 . Central to this aim is the functional characterization of Bcl2L12-mediated inhibition of caspase activity by analyzing its involvement in caspase activating protein complexes and by searching for novel molecules that can interact with Bcl2L12. Specific Aim 2: Molecular characterization of the pro-survival activity of Bcl2L12 . The goal of this aim is to investigate how Bcl2L12 modulates the activities of the major pro-survival signaling cascades known to be involved in gliomagenesis, most notably the Ras/Raf/MAPK, the PI3K/Akt and the Jak signaling pathways. Specific Aim 3: Determination of the in vivo glioma-genic role of Bcl2L12. Bcl2L12 will first be assessed for tumorigenic potential by orthopical injection of mice deficient for INK4a/ARF, a GBM signature lesion, with a retrovirus expressing Bcl2L12 and ultimately by in vivo transgenesis.

• DFG Programme: Emmy Noether International Fellowships
• Host: Dr. Ronald A. DePinho