Genomic and non-genomic pathways are both crucial for peak induction of neurite outgrowth by retinoids

Thabat Khatib, Pietro Marini, Sudheer Nunna, David R. Chisholm, Andrew Whiting, Christopher Redfern, Iain R. Greig, Peter McCaffery (Corresponding Author)

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Abstract

Retinoic acid (RA) is the active metabolite of vitamin A and essential for many physiological processes, particularly the induction of cell differentiation. In addition to regulating genomic transcriptional activity via RA receptors (RARs) and retinoid X receptors (RXRs), non-genomic mechanisms of RA have been described, including the regulation of ERK1/2 kinase phosphorylation, but are poorly characterised. In this study, we test the hypothesis that genomic and non-genomic mechanisms of RA are regulated independently with respect to the involvement of ligand-dependent RA receptors. A panel of 28 retinoids (compounds with vitamin A-like activity) showed a marked disparity in genomic (gene expression) versus non-genomic (ERK1/2 phosphorylation) assays. These results demonstrate that the capacity of a compound to activate gene transcription does not necessarily correlate with its ability to regulate a non-genomic activity such as ERK 1/2 phosphorylation. Furthermore, a neurite outgrowth assay indicated that retinoids that could only induce either genomic, or non-genomic activities, were not strong promoters of neurite outgrowth, and that activities with respect to both transcriptional regulation and ERK1/2 phosphorylation produced maximum neurite outgrowth. These results suggest that the development of effective retinoids for clinical use will depend on the selection of compounds which have maximal activity in non-genomic as well as genomic assays.
Original languageEnglish
Article number40
Number of pages16
JournalCell Communication and Signaling
Volume17
DOIs
Publication statusPublished - 2 May 2019

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Keywords

  • retinoic acid
  • vitamin a
  • Erk1/2
  • neurite outgrowth
  • RAR
  • transcription
  • non-genomic
  • Vitamin a
  • Transcription
  • Non-genomic
  • Retinoic acid
  • Neurite outgrowth

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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