Myc represses the inhibition of Bax/k oligomerization in mitochondrial membranes

• Applicant: Dr. Christian Bernhard Bogner
• Subject Area: Hematology, Oncology
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 166742594

One important cellular response to changes that might lead to cancer is the induction of programmed cell death (apoptosis). Indeed overcoming apoptosis has been identified as one of the critical steps towards carcinogenesis. Bcl-2 is the founding member of a family of proteins sharing 1- 4 homology regions (BH regions) that includes anti-apoptosis proteins such as Bcl-2 and Bcl-XL, proapoptosis proteins such as Bax and Bak as well as BH3 only activator proteins like Bid and Bim. In many cells apoptosis is manifest via activation of Bid to tBid which in turn activates Bax to form pores in mitochondria committing the cell to die. Bcl-2 permits cells to deal with stress by inhibiting pore formation by Bax. A significant body of literature now suggests that regulation of the Bcl-2 family of proteins can restore apoptosis in tumors thereby making them more susceptible to conventional chemotherapy agents. Together tBid and Bax are sufficient to form large pores in liposomes, endoplasmic reticulum and mitochondria membranes. However, mitochondria isolated from c-myc -/- cells are extremely resistant to pore formation by purified tBid and Bax. The aim of this proposal will be to isolate components that inhibit or promote Bax pore formation in vitro by using biochemical fractionation of mitochondrial outer membranes from c-myc -/- and c-myc+ cells. Once identified by mass spectrometry, the apoptotic function of the protein(s) will be validated in cells and in a cell free system established in Dr. Andrews’s lab.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: Dr. David Andrews