Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease.

Loading...
Thumbnail Image

Date

2012-01

Journal Title

Journal ISSN

Volume Title

Repository Usage Stats

127
views
75
downloads

Citation Stats

Abstract

The unfolded protein response, also known as endoplasmic reticulum (ER) stress, has been implicated in numerous human diseases, including atherosclerosis, cancer, diabetes, and neurodegenerative disorders. Protein misfolding activates one or more of the three ER transmembrane sensors to initiate a complex network of signaling that transiently suppresses protein translation while also enhancing protein folding and proteasomal degradation of misfolded proteins to ensure full recovery from ER stress. Gene disruption studies in mice have provided critical insights into the role of specific signaling components and pathways in the differing responses of animal tissues to ER stress. These studies have emphasized an important contribution of translational repression to sustained insulin synthesis and β-cell viability in experimental models of type-2 diabetes. This has focused attention on the recently discovered small-molecule inhibitors of eIF2α phosphatases that prolong eIF2α phosphorylation to reduce cell death in several animal models of human disease. These compounds show significant cytoprotection in cellular and animal models of neurodegenerative disorders, highlighting a potential strategy for future development of drugs to treat human protein misfolding disorders.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/b978-0-12-396456-4.00005-5

Publication Info

Fullwood, Melissa J, Wei Zhou and Shirish Shenolikar (2012). Targeting phosphorylation of eukaryotic initiation factor-2α to treat human disease. Progress in molecular biology and translational science, 106. pp. 75–106. 10.1016/b978-0-12-396456-4.00005-5 Retrieved from https://hdl.handle.net/10161/17238.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Shenolikar

Shirish Shenolikar

Professor Emeritus of Psychiatry and Behavioral Sciences

Protein phosphorylation controls a wide range of physiological processes in mammalian tissues. Phosphorylation state of cellular proteins is controlled by the opposing actions of protein kinases and phosphatases that are regulated by hormones, neurotransmitters, growth factors and other environmental cues. Our research attempts to understand the communication between protein kinases and phosphatases that dictates cellular protein phosphorylation and the cell's response to hormones. Over the last decade, our work has provided critical information about the role of protein phosphatase-1 (PP1) in controlling synaptic function, cell stress, gene expression and growth. We have generated a large repertoire of reagents to decipher PP1's role in signaling pathways in mammalian cells and tissues. Emerging evidence suggests that in many cells, PP1 activity is fine tuned by the protein, inhibitor-1 (I-1). A major focus of our research is to elucidate the role of I-1 in kinase-phosphatase cross-talk and impact of the altered I-1 gene expression seen in several human diseases. Our studies showed that recognition of cellular substrates by PP1 is also directed by its association with a variety of targeting subunits that are themselves also subject to physiological control. Thus, the overall focus of our research is to define the physiological mechanisms that regulate PP1 functions relevant to human health and disease.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.