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Pigment Cell Melanoma Res. 2018 Jan;31(1):51-63. doi: 10.1111/pcmr.12620. Epub 2017 Oct 23.

Genetic variation in IRF4 expression modulates growth characteristics, tyrosinase expression and interferon-gamma response in melanocytic cells.

Author information

1
Dermatology Research Centre, UQ Diamantina Institute, The University of Queensland, TRI, Brisbane, QLD, Australia.
2
School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, at the Translational Research Institute, Brisbane, QLD, Australia.
3
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
4
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia.
5
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Abstract

A SNP within intron4 of the interferon regulatory factor4 (IRF4) gene, rs12203592*C/T, has been independently associated with pigmentation and age-specific effects on naevus count in European-derived populations. We have characterized the cis-regulatory activity of this intronic region and using human foreskin-derived melanoblast strains, we have explored the correlation between IRF4 rs12203592 homozygous C/C and T/T genotypes with TYR enzyme activity, supporting its association with pigmentation traits. Further, higher IRF4 protein levels directed by the rs12203592*C allele were associated with increased basal proliferation but decreased cell viability following UVR, an etiological factor in melanoma development. Since UVR, and accompanying IFNγ-mediated inflammatory response, is associated with melanomagenesis, we evaluated its effects in the context of IRF4 status. Manipulation of IRF4 levels followed by IFNγ treatment revealed a subset of chemokines and immuno-evasive molecules that are sensitive to IRF4 expression level and genotype including CTLA4 and PD-L1.

KEYWORDS:

MITF ; IRF4; UVR response; interferon response; melanocyte; melanoma; tyrosinase

PMID:
28755520
DOI:
10.1111/pcmr.12620

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