Molecular Imaging Division
Mahaveer Swaroop Bhojani
Mahaveer Swaroop Bhojani, PhD: Research Assistant Professor
Fas-Associated protein with Death Domain (FADD) was originally reported as a pro-apoptotic adaptor molecule that mediates receptor induced apoptosis. Our recent studies have revealed a role of FADD in NF-κB activation, embryogenesis, and cell cycle regulation and proliferation. Over-expression of FADD and its phosphorylation have been associated with the transformed phenotype in many cancers and is therefore a potential target for therapeutic intervention. In an effort to delineate signaling events that lead to FADD-phosphorylation and to identify novel compounds that impinge on this pathway, we developed a cell based reporter for FADD-kinase activity. The reporter assay, optimized for high throughput screening, measures bioluminescence in response to modulation of FADD kinase activity within live cells. Initial screens using a library of known kinase-inhibitors identified EGFR activation as an upstream mediator of FADD-phosphorylation. Through the use of FADD null and control mouse embryonic fibroblasts and siRNA knockdown studies we define a role for FADD and phospho-FADD in recruiting an NF-kB inducing complex. These studies provide a link between two key molecular phenotypes in lung and head and neck cancer, EGFR-activation and NF-kB activation and define a role for FADD-phosphorylation in this oncogenic pathway.
Ongoing research is focused on delineating components of the signaling cascade that mediates EGFR-induced FADD-phosphorylation. This is being accomplished using a whole genome siRNA screen against the above described reporter.
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- Amjad P. Khan, Katrina Schienske, Mahaveer S. Bhojani, Brian D. Ross and Alnawaz Rehemtulla. A Live Cell Based Assay for FADD-Kinase activity. J. Biomolecular Screening (In Press)
- Bhojani MS, Chen G, Ross BD, Beer DG, Rehemtulla A. Nuclear localized phosphorylated FADD induces cell proliferation and is associated with aggressive lung cancer. Cell Cycle. 2005 Nov;4(11):1478-81
- Chen G, Bhojani MS, Heaford AC, Chang DC, Laxman B, Thomas DG, Griffin LB, Yu J, Coppola JM, Giordano TJ, Lin L, Adams D, Orringer MB, Ross BD, Beer DG, Rehemtulla A. Phosphorylated FADD induces NF-kappaB, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas. Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12507-12.