• Patrick Dennis

Patrick Dennis's Lab
The laboratory of Patrick Dennis, Assistant Professor, is focused on macroautophagy. Macroautophagy is a basic cellular process in which protein complexes and organelles are sequestered and targeted to the lysosomal compartment for destruction and recycling. In this way, macroautophagy can promote cell survival by providing nutrients during times of need and selectively destroying redundant or damaged organelles, such as mitochondria and portions of the endoplasmic reticulum. However, it is becoming clear that misregulation of macroautophagy can result in a variety of pathologies, including cancer, neurodegeneration and muscle degeneration. Therefore, it is important to understand how cellular stress signals communicate with elements of the macroautophagic machinery. Genetic screens in yeast identified a number of gene products necessary for the induction of different forms of macroautophagy induced in a variety of yeast species. In combination, these screens have identified 27 genes that have been denoted ATG1-27 (for autophagy-related) under a newly adopted nomenclature, and have led to the discovery of numerous mammalian orthologues. Of these orthologues, two have stood out as belonging to potential signaling pathways important for the regulation of mammalian macroautophagy. The mammalian orthologue of Atg6p is the Bcl-2 binding protein, beclin-1, that positively regulates macroautophagy by interacting with the class III PI3K, Vps34. The only protein kinase to be identified in the yeast genetic screens was a serine/threonine kinase, termed Atg1, and two Atg1p orthologues have been identified in mammals and termed ULK1 and 2 (for Unc-51-Like Kinase). The research interest of the Dennis laboratory is to study how cellular stress signals regulate mammalian macroautophagy through beclin 1 and the ULKs. A major part of this research has been to develop new biochemical assays for the measurement of macroautophagy induction. Using known macroautophagy substrates as well as newly-created artificial substrates, novel assays are being developed that are capable of measuring the end-point of the macroautophagic process, that is, lysosomal-based, proteolytic cleavage of the substrate.

Selected Publications:
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