NF1 tumor suppressor in epidermal differentiation and growth - implications for wound epithelialization and psoriasis
1University of Oulu, Faculty of Medicine, Department of Anatomy and Cell Biology
2University of Oulu, Faculty of Medicine, Department of Dermatology and Venereology
|Online Access:||PDF Full Text (PDF, 1 MB)|
|Persistent link:|| http://urn.fi/urn:isbn:9514271106
|Publish Date:|| 2003-08-03
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium of the Department of Anatomy and Cell Biology, on October 3rd, 2003, at 12 noon
Professor Ilkka Harvima
Docent Hannu Järveläinen
Neurofibromatosis type 1 (NF1) is a dominantly inherited neurocutaneous disorder caused by mutations in the NF1 gene. Common clinical manifestations associated with NF1 are neurofibromas, café-au-lait macules (CALM), axillary freckling and Lisch nodules of the iris. Other important manifestations are vasculopathy, a variety of osseous lesions, including short stature, scoliosis and pseudoarthrosis, optic gliomas and an increased risk for certain malignancies. The best characterized function of the NF1 gene is to act as a downregulator of Ras proto-oncogene signalling by accelerating the switch of active Ras-GTP into inactive Ras-GDP. The NF1 gene is considered a tumor suppressor since some malignancies may display a loss of heterozygosity or homozygotic inactivation of the gene.
The present study investigated the behaviour and function of the NF1 gene during keratinocyte differentiation, wound healing and psoriasis using human epidermis and epidermal keratinocytes as a model. The NF1 protein was shown to associate with the intermediate filament network during keratinocyte differentiation both in vitro and in vivo, and it is thus suggested to play a role in the cytoskeletal re-organization or in the formation of cell adhesions. NF1 gene expression was also studied in psoriasis, in which keratinocytes are hyperproliferative and cell differentiation is altered. NF1 gene expression was downregulated in psoriatic keratinocytes both in vivo and in vitro, suggesting that the NF1 gene might have role in downregulating keratinocyte proliferation. During epidermal wound healing, NF1 gene expression was increased. However, the process of wound healing showed no apparent differences between NF1 patients and controls. Furthermore, an increased number of cells immunoreactive for active Ras-MAPK was demonstrated in vascular tissues of NF1 patients, but not in epidermal keratinocytes or dermal fibroblasts. The finding suggests that the NF1 protein functions as a Ras-GAP in some, but not all tissues.
Acta Universitatis Ouluensis. D, Medica
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