The RE-1 silencing transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a master regulator that represses the expression of neuronal genes in stem cell and non-neuronal cells. Overexpression of REST leads to the development of several types of brain tumors, and its dysregulation has been detected in multiple neurological diseases. The huge discrepancy arises reporting different genes subject to REST control, which might be due to the dose- and cell type-dependency of REST in different contexts. In this grant, we will test the hypothesis that REST transcriptional silencing activity can be controlled by small molecule inhibitors of the regulatory protein of REST we have developed. Particularly, we will investigate the cytotoxic effect of these inhibitors in glioblastoma cells when REST drives tumor growth. Furthermore, we will understand at the atomic level the molecular mechanism of REST function through quantitative assessment of its interaction with its DNA targets and its co-repressors for gene silencing. In the long run, we want to identify small molecule inhibitors to treat diseases driven by excess REST activity.

Public Health Relevance

Glioblastoma multiforme (GBM) is the most prevalent and aggress adult brain tumor with a few months of life expectancy once diagnosed. Transcription factor RE1 silencing transcription factor (REST) drives the aggressive growth of the tumor in some patients. Our research utilizes personalized medicine approaches to explore the possibility of a new venue for the intervention of GBM by controlling REST function.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function B Study Section (MSFB)
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Fabian, Miles
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University of Texas Austin
Schools of Arts and Sciences
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Burkholder, Nathaniel Tate; Mayfield, Joshua E; Yu, Xiaohua et al. (2018) Phosphatase activity of small C-terminal domain phosphatase 1 (SCP1) controls the stability of the key neuronal regulator RE1-silencing transcription factor (REST). J Biol Chem 293:16851-16861
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