Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway.
Spitz nevi are benign melanocytic nevi that overlap histopathologically with melanoma. We previously found copy number increases of chromosome 11p frequently paralleled by mutations in the HRAS oncogene mapping to this region. In this study, we explored mechanisms that inhibit proliferation in the presence of HRAS activation. We analyzed MAP-kinase activation using immunohistochemistry for phospho-ERK, cyclin D1, and microphthalmia transcription factor expression in 17 Spitz nevi with and 18 Spitz nevi without 11p copy number increase. We found relatively high levels of phospho-ERK and cyclin D1 expression suggesting MAP-kinase pathway activation in both groups of Spitz nevi. However, Spitz nevi with 11p copy number increases showed significantly higher levels of cyclin D1 expression and lower levels of microphthalmia transcription factor expression suggesting stronger MAP-kinase pathway activation in this group. Contrasting this apparent activation, the proliferation rate as assessed by Mib1 expression was low in both groups. An analysis of cell-cycle inhibitory proteins including p16, p21, and p27 showed that the majority of Spitz nevus cells expressed high levels of p16, with cells of the cases that had increased copy number of 11p expressing significantly higher levels than those of Spitz nevi with normal copy number of 11p. We propose that in benign nevi with constitutive activation of the MAP-kinase pathway, p16 functions as an essential mediator of oncogene-induced senescence preventing progression to melanoma.
Maldonado
Janet L
JL
Department of Dermatology, University of California, San Francisco, California 94143, USA.
Timmerman
Luika
L
Fridlyand
Jane
J
Bastian
Boris C
BC
D002138:Calibration; D002453:Cell Cycle; D002455:Cell Division; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018332:Nevus, Epithelioid and Spindle Cell / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis
D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D014157:Transcription Factors; D019938:Cyclin D1; D020928:Mitogen-Activated Protein Kinases