Aug 18, 2018

In vitro behavior and UV response of melanocytes derived from carriers of CDKN2A mutations and MC1R variants

Pigment Cell & Melanoma Research
Barbara HernandoZalfa A Abdel-Malek

Abstract

Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different CDKN2A mutation carriers, expressing either wild-type MC1R or MC1RLOF variant(s). These cultures expressed the CDKN2A product p16 (INK4A) and functional MC1R. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence. Additionally, the latter cultures responded normally to ultraviolet radiation (UV) by cell cycle arrest, JNK, p38, and p53 activation, hydrogen peroxide generation, and repair of DNA photoproducts. We propose that malignant transformation of melanocytes expressing CDKN2A mutation and MC1RLOF allele(s) requires acquisition of somatic mutations facilitated by MC1R genotype or aberrant microenvironment due to CDKN2A mutation in keratinocytes and fibroblasts.

  • References44
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  • References44
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Citations

Mentioned in this Paper

Cyclin-Dependent Kinase Inhibitor Proteins
Melanocyte
Cell Aging
Hydrogen Peroxide
Germ-Line Mutation
Specimen Type - Fibroblasts
MC1R Protein
Keratinocyte
Somatic Mutation
Cyclin-Dependent Kinase Inhibitor p16

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