The role of a ubiquitin ligase adaptor protein in glucose homeostasis and beta cell mass / Kathryn Carver Claiborn.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Claiborn, Kathryn Carver.

Contributor:

Stoffers, Doris A., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Cell and Molecular Biology.

Academic Dissertations as Topic.

Medical Subjects:

Cell and Molecular Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

ix, 109 pages : illustrations ; 29 cm

Production:

2009.

Summary:

The homeodomain transcription factor Pdx1 plays a critical role in pancreas development and in the differentiation and maintenance of adult beta cells. Thus, the regulation of Pdx1 protein levels is of intense interest in the study of diabetes. Pharmacological strategies to manipulate Pdx1 protein levels in adult beta cells could improve beta cell function and prevent beta cell death. Furthermore, an understanding of the biological processes that promote beta cell development could be capitalized upon in a cell-therapy approach for diabetes treatment. Our laboratory previously identified Pdx1 C-terminus Interacting Factor 1 (Pcif1), a nuclear protein that interacts with Pdx1 and inhibits Pdx1 transactivation. In this work, I explore the function of Pcif1 in both adult beta cells and in pancreas development. In chapter 2, I describe cell-based experiments that establish the role of Pcif1 as a ubiquitin ligase substrate adaptor that targets Pdx1 for proteasomal degradation. I further describe the derivation of a strain of mice heterozygous for Pcif1 (Pcif1gt), and demonstrate a role for Pcif1-mediated Pdx1 modulation in vivo. In chapter 3, I investigate the role of Pcif1 in pancreas development and differentiation of the pancreatic endocrine and exocrine compartments by analyzing the phenotype of Pcif1gt/gt mice. Cumulatively, this work demonstrates that Pcif1 is a modulator of Pdx1 protein accumulation in vivo, thus contributing the function and survival of adult beta cells and normal pancreas development. Finally, chapter 4 details the functional characterization of a novel Pdx1 mutation that results in neonatal diabetes in humans, and provides evidence that in addition to normal protein levels, Pdx1 transcriptional activity is required for normal glucose homeostasis.

Notes:

Adviser: Doris A. Stoffers.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2009.

Includes bibliographical references.