Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. Christopher L. Pin

Abstract

Pancreatitis is characterized by inappropriate activation of digestive enzyme

precursors, or zymogens, local and systemic inflammation, dysregulation of

cellular calcium (Ca2+), and induction of the unfolded protein response (UPR).

The UPR consists of three distinct pathways all of which are activated during

pancreatitis. However, the molecular roles of each remain unclear. The

protein kinase RNA (PKR)-like ER kinase (PERK) pathway reduces general

protein translation by phosphorylating eIF2!, and is activated within minutes

of initiating pancreatic damage. Microarray analysis carried out by our lab

revealed robust upregulation of the PERK pathways members Activating

Transcription Factor (ATF) 3 and stanniocalcin (STC) 2. The roles of ATF3

and STC2 within the context of PERK signaling and pancreatitis are not well

known. Thus, the goal of this study was to define the roles of STC2 and

ATF3 during pancreatitis. Gene expression analysis revealed significant

increases in STC2 during cerulein induced pancreatitis (CIP) and mice

overexpressing STC2 (STC2Tg) exhibited decreased pancreatitis severity as

evidenced by the maintenance of acinar cell differentiation markers, lower

levels of serum amylase compared to wild type (WT) and a decreased

necrosis to apoptosis ratio. Conversely, ATF3 appears to function in an

opposite fashion to STC2 during pancreatitis. Chromatin immunoprecipitation

(ChIP) of pancreatic tissue following CIP showed that ATF3 bound the Mist1

promoter, recruited Histone Deacteylasee (HDAC) 5 and repressed Mist1

expression, leading to loss of the acinar cell phenotype. Human and mouse

pancreatitis tissue samples reveal mutually exclusive expression of ATF3 and

MIST1, illustrating clinical relevance for ATF3. Mice lacking Atf3 (Atf3-/-)

exhibited a similar phenotype to STC2Tg mice, with increased maintenance of

cellular junctions and cell polarity. These findings suggest that these

mediators of the PERK pathway lead to opposing outcomes, and that this

pathway plays a dual role of both protection and injury during pancreatitis.

Share

COinS