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

Bowles, Kathryn R., Stone, Timothy C. ORCID: https://orcid.org/0000-0003-4591-9611, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412, Allen, Nicholas Denby ORCID: https://orcid.org/0000-0003-4009-186X, Dunnett, Stephen Bruce ORCID: https://orcid.org/0000-0003-1826-1578 and Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612 2017. SMAD transcription factors are altered in cell models of HD and regulate HTT expression. Cellular Signalling 31 , pp. 1-14. 10.1016/j.cellsig.2016.12.005

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine Advanced Research Computing @ Cardiff (ARCCA) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Huntington's Disease; Transcription; EGF; TGF-beta; SMAD; Kinase signalling
Publisher:	Elsevier
ISSN:	0898-6568
Funders:	Wellcome Trust, European Huntington's Disease Network
Date of First Compliant Deposit:	20 December 2016
Date of Acceptance:	12 December 2016
Last Modified:	16 May 2023 20:35
URI:	https://orca.cardiff.ac.uk/id/eprint/96994

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