Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway
| Autor: | Janet L. Maldonado, Jane Fridlyand, Boris C. Bastian, Luika A. Timmerman |
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| Rok vydání: | 2004 |
| Předmět: |
Cell cycle checkpoint
MAP Kinase Signaling System Biology Microphthalmia Pathology and Forensic Medicine Cyclin D1 Nevus Epithelioid and Spindle Cell medicine Humans HRAS skin and connective tissue diseases Melanoma Microphthalmia-Associated Transcription Factor Oncogene integumentary system Cell Cycle Cell cycle medicine.disease Spitz nevus Immunohistochemistry DNA-Binding Proteins Enzyme Activation Calibration Cancer research Disease Progression Mitogen-Activated Protein Kinases Cell Division Transcription Factors Regular Articles |
| Zdroj: | The American journal of pathology. 164(5) |
| ISSN: | 0002-9440 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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