Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis
2010
We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse
melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway
mutations cooperated with NrasQ61K to transform MCs. We previously reported that MCs migrate from the
follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly
diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4R24C did not affect the MC migration. Instead, independent of UVR exposure,
interfollicular dermal MCs were more prevalent in Cdk4R24C mice. Subsequently, in adulthood, these mutants
developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were
observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.
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