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Cell Signal. 2017 Feb;31:1-14. doi: 10.1016/j.cellsig.2016.12.005. Epub 2016 Dec 14.

SMAD transcription factors are altered in cell models of HD and regulate HTT expression.

Author information

1
The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: kathryn.bowles@mssm.edu.
2
The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: stonetc@cardiff.ac.uk.
3
The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: holmanspa@cardiff.ac.uk.
4
Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK. Electronic address: allennd@cardiff.ac.uk.
5
The Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK. Electronic address: dunnettsb@Cardiff.ac.uk.
6
The MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff CF24 4HQ, UK. Electronic address: jonesl1@cardiff.ac.uk.

Abstract

Transcriptional dysregulation is observable in multiple animal and cell models of Huntington's disease, as well as in human blood and post-mortem caudate. This contributes to HD pathogenesis, although the exact mechanism by which this occurs is unknown. We therefore utilised a dynamic model in order to determine the differential effect of growth factor stimulation on gene expression, to highlight potential alterations in kinase signalling pathways that may be in part responsible for the transcriptional dysregulation observed in HD, and which may reveal new therapeutic targets. We demonstrate that cells expressing mutant huntingtin have a dysregulated transcriptional response to epidermal growth factor stimulation, and identify the transforming growth factor-beta pathway as a novel signalling pathway of interest that may regulate the expression of the Huntingtin (HTT) gene itself. The dysregulation of HTT expression may contribute to the altered transcriptional phenotype observed in HD.

KEYWORDS:

EGF; Huntington's Disease; Kinase signalling; SMAD; TGF-beta; Transcription

PMID:
27988204
PMCID:
PMC5310119
DOI:
10.1016/j.cellsig.2016.12.005
[Indexed for MEDLINE]
Free PMC Article

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