Date of Award

Fall 2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Science

First Advisor

Stephen F. Konieczny

Committee Chair

R. Claudio Aguilar

Committee Member 1

Stephen F. Konieczny

Committee Member 2

Julia Kirshner

Committee Member 3

Sophie Lelievre

Abstract

Pancreatic acinar cells (PACs) continuously produce more protein than any other cell type in the human body. As a result, PACs and other specialized secretory cells have a constant demand placed on their protein synthetic and packaging machinery. When demand for secreted products exceeds the capacity of the cell's basal protein production facilities, dangerous accumulations of misfolded proteins can build up, resulting in a condition known as ER stress. To ameliorate this stress, secretory cells activate a coordinated, three-part compensatory network collectively known as the unfolded protein response (UPR) to both expand the capacity of the ER and directly assist in refolding or degradation of aberrant peptides. Interestingly, others have hypothesized that the UPR branches largely overlap in their functions and targets, prompting us to investigate whether loss of the IRE1/XBP1 branch via conditional ablation of XBP1 in mature mouse PACs could be compensated for by the remaining UPR pathways. We show that survival and homeostasis of PACs is wholly dependent on the IRE1/XBP1 axis of the UPR. Specifically, ablation of Xbp1 in mouse PACs results in a gradual but cumulative onset of irreversible ER stress. This results in abrogation of normal digestive enzyme synthesis, onset of extensive signs of pancreatic distress, and eventual apoptosis via ER stress-induced death pathways. Remarkably, we also show that the pancreas initiates a robust regenerative response via cell cycle reentry and proliferation of multiple adult cell types. This regenerative mechanism rapidly restores a functioning exocrine compartment and provides a novel means to study pancreatic damage and recovery from intrinsic stress events. Finally, we investigated the role of the acinar cell-specific transcription factor MIST1 as a downstream effector of XBP1. We verify that MIST1 is a direct target of XBP1, and a number of MIST1 target genes directly participate in facilitating cell recovery and survival during ER stress. Together, these data indicate that XBP1 and MIST1 cooperate to sustain pancreatic acinar cells during times of high protein demand. Future disease research exploiting stress induction via modulation of the XBP1/MIST1 transcriptional network may be used to generate novel therapeutics for treatment of pancreatitis and pancreatic cancer.

Download

Included in

Cell Biology Commons

Share

COinS