Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis.
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.
Ferguson
Blake
B
Skin Carcinogenesis Laboratory, Queensland Institute of Medical Research, Herston, Qld, Australia.
Konrad Muller
H
H
Handoko
Herlina Y
HY
Khosrotehrani
Kiarash
K
Beermann
Friedrich
F
Hacker
Elke
E
Soyer
H Peter
HP
Bosenberg
Marcus
M
Walker
Graeme J
GJ
D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002465:Cell Movement / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D008544:Melanocytes / Q000473:pathology / Q000528:radiation effects; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009506:Nevus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019683:Penetrance; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4