Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


osu1116425282.pdf (10.88 MB)

ETD Abstract Container

Abstract Header

The roles of ATF3 in stress-regulated signal transduction and cell death in pancreatic beta-cells

Hartman, Matthew George
http://rave.ohiolink.edu/etdc/view?acc_num=osu1116425282

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
Activating Transcription Factor 3 (ATF3) is a member of the ATF/CREB family of bZip domain-containing transcription factors. Previous studies demonstrated that most cells contain minimal endogenous ATF3 levels; however, ATF3 upregulation was observed in most cell types following treatment with a variety of stress signals. Work presented in this thesis describes the induction, functional consequences of expression, and mechanism of action of ATF3 in pancreatic â-cells. Data presented in chapter 2 demonstrates ATF3 upregulation in â-cell lines by stress signals relevant to type 1 (pro-inflammatory cytokines) and type 2 diabetes (free fatty acids, hyperglycemia, oxidative stress). In addition, elevated ATF3 protein levels were detected in pancreatic islets from a type 1 diabetic mouse model (NOD) and both type 1 and 2 human patient tissues. Investigation of the signal transduction pathways involved in ATF3 induction revealed that both the JNK and NFêB pathways are required for optimal ATF3 expression following IL-1â treatment. Using gain-of-function and loss-of-function approaches, data presented in chapter 3 describes a pro-apoptotic role for ATF3 during the stress response. First, ectopic ATF3 expression targeted to pancreatic â-cells during development resulted in mice displaying decreased islet area, high blood glucose levels, decreased serum insulin levels, and markers indicative of â-cell failure (elevated ketone bodies). Second, primary islets purified from ATF3 knock out mice were partially protected from cytokine-induced apoptosis. Chapter 4 investigates the potential cross-talk and functional interaction between ATF3 and Akt in â-cells. Results reveal that inhibition of ATF3 expression by activated Akt represents a novel mechanism whereby Akt promotes â-cell survival. In support of this notion, expression of ATF3 almost completely reversed the anti-diabetic phenotype of the constitutively-active Akt transgenic mice. Insights into the mechanism of ATF3-induced cell death suggest that ATF3 may promote apoptosis by triggering activation of the intrinsic (mitochondrial) death pathway.
Tsonwin Hai (Advisor)
209 p.
Biology, Molecular
ATF3; diabetes; beta-cell death

Recommended Citations

Citations

  • Hartman, M. G. (2005). The roles of ATF3 in stress-regulated signal transduction and cell death in pancreatic beta-cells [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1116425282

    APA Style (7th edition)

  • Hartman, Matthew. The roles of ATF3 in stress-regulated signal transduction and cell death in pancreatic beta-cells. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1116425282.

    MLA Style (8th edition)

  • Hartman, Matthew. "The roles of ATF3 in stress-regulated signal transduction and cell death in pancreatic beta-cells." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1116425282

    Chicago Manual of Style (17th edition)

osu1116425282
1,558
© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.