Beta2 is a critical regulator of differentiation and survival of several neuro-endocrine cell types including the pancreatic beta cell, neurons and entero-endocrine cells, such that mice lacking Beta2 display severe diabetes, neuronal depletion and neonatal death. In pancreatic beta cells, Beta2 is one of the key regulators of glucose-dependent insulin gene expression, suggesting a homeostatic role of Beta2 in mature beta cells. While it is clear that Beta2 has multiple functions in both developing and mature neuro-endocrine cells, little is known about how its activity is regulated in different cellular contexts. Transcription factors that orchestrate such an important array of functions are usually tightly regulated post-translationally by highly specific, rapid and reversible covalent modifications. Recent studies suggest that Beta2 function can be regulated by phosphorylation of its transactivation domain. Here we propose to examine the effects of acetylation on Beta2. Beta2 associates with p300, a transcriptional coactivator with an intrinsic acetyltransferase (AT) enzymatic activity, and this association is required for inducing differentiation and glucose-dependent insulin gene activation. Therefore, we examined whether Beta2 is a substrate for p300 dependent AT activity and found this to be true both by in vitro acetylation assay, and in transfected cells. Based on our preliminary data, we hypothesize that acetylation of Beta2 plays an important role in regulation of its activity. The main goal of this study is to examine the impact of acetylation on Beta2 function. To address this question, we propose to: 1) Identify the specific lysine residues that undergo p-300 dependent acetylation, in vitro and in vivo; 2) Assess the impact of acetylation on the mechanism of Beta2; and 3) Examine the biological significance of Beta2 acetylation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK066203-02
Application #
6835619
Study Section
Metabolism Study Section (MET)
Program Officer
Sato, Sheryl M
Project Start
2003-12-15
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2006-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$123,108
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093