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Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis
Author(s) -
Ferguson Blake,
Konrad Muller H.,
Handoko Herlina Y.,
Khosrotehrani Kiarash,
Beermann Friedrich,
Hacker Elke,
Peter Soyer H.,
Bosenberg Marcus,
Walker Graeme J.
Publication year - 2010
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2010.00752.x
Subject(s) - melanoma , cancer research , differential (mechanical device) , biology , medicine , pathology , engineering , aerospace engineering
Summary 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 Nras Q61K 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. Cdk4 R24C did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4 R24C 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.