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Autophagic cell death across Kingdoms; using the plant genetic model system Arabidopsis to characterize cell death regulators in animals, with applications for human cancer (Kingdom Cell Death)
Start date: 01 Jan 2009, End date: 31 Mar 2011 PROJECT  FINISHED 

Programmed cell death (PCD) is essential for plant and animal development. PCD is also invoked in pathological physiologies, as inappropriate PCD is implicated in human disease, while PCD is required for the plants innate immune response to pathogens. One type of PCD, macroautophagy, is an intracellular degradation system for cytosolic components and organelles in eukaryotes. The molecular mechanism of autophagy, although extensively studied using yeast during the past decade, remains to be elucidated. Similarly, plants undergo authophagic cell death – the genetically tractable model plant Arabidopsis thaliana represents a superior platform for understanding this process in higher eukaryotes. The recently discovered accelerated cell death 11 (acd11) mutant, a deletion of a sphingolipid transfer protein, exhibits vegetative cell death that is blocked if depleted of the defense molecule salicylic acid. Preliminary data shows that ACD11 and its human homolog FAPP2 suppress autophagy, indicating that they function in a cell death pathway conserved across the eukaryotic kingdoms. This is of extraordinary interest, since it provides a genetic tool to rapidly identify new regulators of human autophagy in Arabidopsis. Therefore, genetic screening and cloning of PCD suppressors from acd11 and related mutants, and the identification of ACD11 interaction partners, will allow us to characterize novel positive and negative regulators of PCD across kingdoms. The identification of the candidate human PCD regulator hsPRA1 by screening for ACD11-interactors in Arabidopsis is an exciting advance and points toward the validity of this approach. Furthermore, truncated versions of FAPP2 accumulate in various cancers. Our goal is to investigate the oncogenic potential of FAPP2 and novel PCD regulators in human autophagy and cancer transformation. Autophagic cell death induction by some anticancer agents underlines the potential utility of its induction as a new cancer treatment modality.
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