UC San Diego

Progression through the cell cycle adapts to both internal and environmental stimuli to ensure fidelity of cell division. Endoplasmic reticulum (ER) stress arising from an imbalance between cellular demand for protein folding and ER capacity has been described to cause G1 cell cycle arrest. The molecular components of this ER stress checkpoint have just begun to be uncovered. Although evidence emerge to suggest a prosurvival role for the ER stress-induced cell cycle arrest, the functional significance of this checkpoint in mammalian cells largely remains as an open question. Given the implication of ER stress in multiple human diseases like cancer and neurological disorders, elucidation of the link between ER stress and cell cycle may provide new insights to the pathogenesis and treatment of these diseases. In Chapter 1, I introduce the principles of cell cycle regulation and checkpoint responses, leading to a discussion on the discoveries that support an emerging ER stress checkpoint in eukaryotic cells. In Chapter 2, I investigate the mechanisms underlying cell cycle delay in G1 in response to ER stress in mammalian cells, showing that ER stress reduces the protein expression of Skp2 by downregulating Ufd1, a protein that stabilizes Skp2 through its ability to recruit the deubiquitinating enzyme USP13. This results in an accumulation of p27 that partly contributes to G1 arrest in ER-stressed cells. In Chapter 3, I identify another regulator of the ER stress checkpoint, APC/C-Cdh1, and begin to examine the upstream signals responsible for activating APC/C-Cdh1 under ER stress conditions. In Chapter 4, I provide a summary of the work and discuss the implications of my findings