Identification and Functional Analysis of O-G1cNAc Glycosylation on the Transcription Factor cAMP-Response Element Binding Protein

Citation

Lamarre-Vincent, Nathan (2007) Identification and Functional Analysis of O-G1cNAc Glycosylation on the Transcription Factor cAMP-Response Element Binding Protein. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/ZEXB-6889. https://resolver.caltech.edu/CaltechETD:etd-05292007-183523

Abstract

The survival and development of organisms requires the ability of cells to communicate with the environment and with surrounding cells. This demand has led to the evolution of a number of methods used for communication. Chief among these is the ability to modify protein function with post-translational modifications (PTMs). PTMs allow cells to use a single protein for a variety of tasks and link protein activity with a specific environmental or cellular cue. Modification of transcription factors has arisen as a key model for the study of PTMs and their effects on cell processes. PTMs modulate transcriptional activity required for key processes such as development, differentiation and cell survival.

The eukaryotic transcription factor cAMP-response element binding protein (CREB) is a transcription factor that confers dynamic control of a number of cellular processes including neuronal and pancreatic cell survival, gluconeogenesis and neuronal long-term potentiation. CREB is activated by phosphorylation of single serine residue. The observation that a number of kinase signaling cascades converge on CREB has led to the question of how cells deal with the apparent loss of signal identity that occurs as a result of this convergence. In this thesis I describe the identification, characterization and functional analysis of a novel PTM of CREB, O-GlcNAc glycosylation, that provides an additional level of control of CREB activity. CREB glycosylation moderates phosphorylation-dependent CREB activity and reduces CREB-dependent gene expression in pancreatic [beta]-cells, and as a result promotes [beta]-cell death, as observed in type II diabetes. CREB glycosylation offers us an example of how cells use multiple PTMs to control protein function and how dysfunction in the regulation of these modifications may contribute to disease states.

Thesis Files