The Role of BRAF Mutation and p53 Inactivation during Transformation of a Subpopulation of Primary Human Melanocytes
| Autor: | Phyllis A. Gimotty, Hong Yu, Patricia A. Possik, Mcdaid Ronan, John T. Lee, Maria Dalla Palma, David E. Elder, K. L. Nathanson, Matthew Guerra, Patricia Van Belle, Suresh M. Kumar, Ling Li, Meenhard Herlyn, Xiaowei Xu, Rachel Hammond |
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| Rok vydání: | 2009 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Senescence Skin Neoplasms Nevi and melanomas Tumor suppressor gene Blotting Western Gene Expression Mice SCID Melanocyte Biology Polymerase Chain Reaction Retinoblastoma Protein Pathology and Forensic Medicine Malignant transformation Mice medicine Animals Humans Melanoma Cells Cultured Cellular Senescence Oligonucleotide Array Sequence Analysis Comparative Genomic Hybridization Gene Expression Profiling medicine.disease Immunohistochemistry Gene expression profiling Cell Transformation Neoplastic medicine.anatomical_structure Mutation Cancer research Melanocytes Tumor Suppressor Protein p53 V600E Regular Articles |
| Zdroj: | The American Journal of Pathology. 174:2367-2377 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2009.081057 |
| Popis: | Melanocytic nevi frequently harbor oncogenic BRAF mutations, but only a minority progress to melanoma. In human melanocytes, persistent BRAF(V600E) expression triggers oncogene-induced senescence, which implies that bypass of oncogene-induced senescence is necessary for malignant transformation of melanocytes. We show that a subpopulation of primary human melanocytes with persistent expression of BRAF(V600E) do not enter oncogene-induced senescence, but instead survive despite heightened MAPK activity. Disruption of the p53 pathway using short-hairpin RNA initiated rapid growth of these V600E(+) melanocytes in vitro. The resultant V600E(+)/p53(sh) melanocytes grew anchorage-independently in soft agar, formed pigmented lesions reminiscent of in situ melanoma in artificial skin reconstructs, and were weakly tumorigenic in vivo. Array comparative genomic hybridization analysis demonstrated that the transformed melanocytes acquired a substantial deletion in chromosome 13, which encodes the Rb1 tumor suppressor gene. Gene expression profiling study of nevi and melanomas showed that p53 target genes were differentially expressed in melanomas compared with nevi, suggesting a dysfunctional p53 pathway in melanoma in vivo. In summary, these data demonstrate that a subpopulation of melanocytes possesses the ability to survive BRAF(V600E)-induced senescence, and suggest that p53 inactivation may promote malignant transformation of these cells. |
| Databáze: | OpenAIRE |
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