THE HYPOXIA INDUCIBLE BCL 2 HOMOLOGUE BNIP3 IS MUTATED IN OLIGODENDROGLIAL TUMORS S. Zhang,one A. Perry,two F. Xue,1 E. Henson,1 S. B. Gibson,1 D. D. Eisenstat1, one Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, MB, Canada, 2Department of Pathology, Washington University, St. Louis, MO, USA Oligodendroglial tumors are classified as oligodendrogliomas or anaplastic oligodendroglio mas. A lack of response to therapy may very well be resulting from tumor hypoxia, which facilitates resistance to radiation and chemotherapy. The BCL2 19 kilodalton interacting protein is actually a BCL two family member which is upregulated in hypoxic areas in many tumors. BNIP3 is straight activated from the transcription component HIF1A and mediates cell death in a caspase independent method with the interaction of its transmembrane domain with mitochondria. We have established that BNIP3 is upregulated in oligodendroglial tumors in contrast with normal brain tissue.
This enhanced BNIP3 expression was correlated with increased HIF1A and glut one, indicating selleck hypoxic areas inside these tumors. In 17% of key GBMs, we detected mutations in the PEST domain of BNIP3 that targets BNIP3 to the proteosome. These BNIP3 mutations result in a truncated protein that lacks a functional TM domain. We sequenced the Dutasteride BNIP3 gene in 45 oligodendroglial tumors and uncovered mutations in 10. In 21 of 24 AO tumors examined, we observed predominantly nuclear expression of BNIP3. Overexpression of BNIP3 in glioma cells induced cell death, whereas therapy with mutant BNIP3 blocked hypoxia induced cell death. This blockage of cell death was attributable to the failure of BNIP3 to localize on the mitochondria and inhibition of BNIP3 mediated mitochondrial dysfunction. Our discovery suggests that BNIP3 perform might be abrogated in OD tumors, both by sequestration inside the nucleus or inactivating mutations.
This might explain why solutions for ODs are frequently ineffective in hypoxic areas of these tumors. CB 42. REGULATION OF FAK BY Ras IN BRAIN METASTASES OF BREAST CANCER CELLS Yanhua Zheng, Dexing Fang, Yan Xia, and Zhimin Lu, Division of Neuro Oncology and Molecular Genetics, The University of Texas M. D. Anderson Cancer, Houston, TX, USA Brain metastases from breast cancer are prevalent and induce http://t.co/MfAIst4oCe

— Lasyaf Hossain (@lasyafhossain) November 8, 2013

significant morbidity and mortality, but their underlying mechanism is still largely unknown. We discovered that brain metastatic breast cancer cells had higher Ras activity, corresponding to a reduced FAK phosphorylation level than that identified in parental breast cancer cells. Dephosphorylation and inhibi tion of FAK was dependent on Ras activity and mediated by Cdc42 but not other Ras downstream signaling molecules, such as Raf, PI 3K, Ral, and Rac. Furthermore, overexpression of the wild type tyrosine phosphatase PTP PEST, but not its catalytic domain mutant, dephosphorylated FAK.