THE HYPOXIA INDUCIBLE BCL two HOMOLOGUE BNIP3 IS MUTATED IN OLIGO

THE HYPOXIA INDUCIBLE BCL 2 HOMOLOGUE BNIP3 IS MUTATED IN OLIGODENDROGLIAL TUMORS S. Zhang,one A. Perry,2 F. Xue,1 E. Henson,1 S. B. Gibson,one D. D. Eisenstat1, 1 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 treatment may very well be because of tumor hypoxia, which facilitates resistance to radiation and chemotherapy. The BCL2 19 kilodalton interacting protein is known as a BCL 2 relatives member that is upregulated in hypoxic areas in many tumors. BNIP3 is straight activated by the transcription element HIF1A and mediates cell death inside a caspase independent method through the interaction of its transmembrane domain with mitochondria. We now have established that BNIP3 is upregulated in oligodendroglial tumors in contrast with usual brain tissue.
This increased BNIP3 expression was correlated with improved HIF1A and glut one, indicating selleckchem hypoxic areas inside of these tumors. In 17% of main GBMs, we detected mutations in the PEST domain of BNIP3 that targets BNIP3 on the proteosome. These BNIP3 mutations lead to a truncated protein that lacks a functional TM domain. We sequenced the ARRY334543 BNIP3 gene in 45 oligodendroglial tumors and uncovered mutations in ten. In 21 of 24 AO tumors examined, we noticed predominantly nuclear expression of BNIP3. Overexpression of BNIP3 in glioma cells induced cell death, whereas treatment method with mutant BNIP3 blocked hypoxia induced cell death. This blockage of cell death was brought on by the failure of BNIP3 to localize for the mitochondria and inhibition of BNIP3 mediated mitochondrial dysfunction. Our discovery suggests that BNIP3 perform could possibly be abrogated in OD tumors, both by sequestration in the nucleus or inactivating mutations.
This could clarify why solutions for ODs are often ineffective in hypoxic regions 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 result in

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 found 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.

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