Skip to main content

Advertisement

SpringerLink
Log in

NF1 tumor suppressor in epidermal wound healing with special focus on wound healing in patients with type 1 neurofibromatosis

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Type 1 neurofibromatosis syndrome (NF1) has been linked with mutations of the NF1 gene which encodes tumor suppressor neurofibromin, a regulator of Ras-MAPK signaling. In human epidermis, keratinocytes express NF1 tumor suppressor and it may have a distinctive function in these cells during wound healing, such as regulating Ras activity. NF1 expression was first studied during the epidermal wound healing using suction blister method. NF1 gene expression increased both in hypertrophic and migrating zones of the healing epidermis, and also in dermal fibroblasts underneath the injury. This prompted us to study epidermal wound healing in NF1 patients. Wound healing efficiency was evaluated 4 days after blister induction by clinical, physiological and histological methods. Epidermal wound healing was equally effective in NF1 patients and healthy controls. In addition, dermal wound healing appears to function normally in NF1 patients based on retrospective and follow-up study of biopsy scars. Furthermore, the healing wounds were analyzed immunohistochemically for cell proliferation rate and Ras-MAPK activity. Neither epidermal keratinocytes nor dermal fibroblasts showed difference in the cell proliferation rate or Ras-MAPK activity between NF1 patients and controls. Interestingly, NF1 patients displayed increased cell proliferation rate and Ras-MAPK activity in periarteriolar tissue underneath the wound. The results of the study suggest that epidermal wound healing is not markedly altered in NF1 patients. Furthermore, NF1 protein seems not to have an important function as a Ras-MAPK regulator in epidermal keratinocytes or dermal fibroblasts but instead appears to be regulator of Ras-MAPK signaling in vascular tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Gutmann DH, Wood DL, Collins FS (1991) Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci USA 88:9658–9662

    CAS  PubMed  Google Scholar 

  2. Marchuk DA, Saulino AM, Tavakkol R, Swaroop M, Wallace MR, Andersen LB, Mitchell AL, Gutmann DH, Boguski M, Collins FS (1991) cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11:931–940

    CAS  PubMed  Google Scholar 

  3. Riccardi VM (1981) Von Recklinghausen neurofibromatosis. N Engl J Med 305:1617–1627

    CAS  PubMed  Google Scholar 

  4. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Jama 278:51–57

    CAS  PubMed  Google Scholar 

  5. Legius E, Marchuk DA, Collins FS, Glover TW (1993) Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet 3:122–126

    CAS  PubMed  Google Scholar 

  6. Metheny LJ, Cappione AJ, Skuse GR (1995) Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I. J Neuropathol Exp Neurol 54:753–760

    CAS  PubMed  Google Scholar 

  7. Li Y, Bollag G, Clark R, Stevens J, Conroy L, Fults D, Ward K, Friedman E, Samowitz W, Robertson M et al (1992) Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell 69:275–281

    CAS  PubMed  Google Scholar 

  8. Johnson MR, Look AT, DeClue JE, Valentine MB, Lowy DR (1993) Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP Ras. Proc Natl Acad Sci USA 90:5539–5543

    CAS  PubMed  Google Scholar 

  9. Gutmann DH, Geist RT, Rose K, Wallin G, Moley JF (1995) Loss of neurofibromatosis type I (NF1) gene expression in pheochromocytomas from patients without NF1. Genes Chromosomes Cancer 13:104–109

    CAS  PubMed  Google Scholar 

  10. Aaltonen V, Bostrom PJ, Soderstrom KO, Hirvonen O, Tuukkanen J, Nurmi M, Laato M, Peltonen J (1999) Urinary bladder transitional cell carcinogenesis is associated with down-regulation of NF1 tumor suppressor gene in vivo and in vitro. Am J Pathol 154:755–765

    CAS  PubMed  Google Scholar 

  11. Hermonen J, Hirvonen O, Yla-Outinen H, Lakkakorpi J, Bjorkstrand AS, Laurikainen L, Kallioinen M, Oikarinen A, Peltonen S, Peltonen J (1995) Neurofibromin: expression by normal human keratinocytes in vivo and in vitro and in epidermal malignancies. Lab Invest 73:221–228

    CAS  PubMed  Google Scholar 

  12. Peltonen J, Karvonen SL, Yla-Outinen H, Hirvonen O, Karvonen J (1995) Lesional psoriatic epidermis displays reduced neurofibromin immunoreactivity. J Invest Dermatol 105:664–667

    CAS  PubMed  Google Scholar 

  13. Gutmann DH, Loehr A, Zhang Y, Kim J, Henkemeyer M, Cashen A (1999) Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation. Oncogene 18:4450–4459

    CAS  PubMed  Google Scholar 

  14. Xu GF, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R, Tamanoi F (1990) The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 63:835–841

    CAS  PubMed  Google Scholar 

  15. Basu TN, Gutmann DH, Fletcher JA, Glover TW, Collins FS, Downward J (1992) Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356:713–715

    CAS  PubMed  Google Scholar 

  16. Bollag G, McCormick F (1992) Ras regulation. NF is enough of GAP. Nature 356:663–664

    CAS  PubMed  Google Scholar 

  17. DeClue JE, Papageorge AG, Fletcher JA, Diehl SR, Ratner N, Vass WC, Lowy DR (1992) Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69:265–273

    CAS  PubMed  Google Scholar 

  18. Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351(Pt 2):289–305

    CAS  PubMed  Google Scholar 

  19. Johnson MR, DeClue JE, Felzmann S, Vass WC, Xu G, White R, Lowy DR (1994) Neurofibromin can inhibit Ras-dependent growth by a mechanism independent of its GTPase-accelerating function. Mol Cell Biol 14:641–645

    CAS  PubMed  Google Scholar 

  20. Li Y, White R (1996) Suppression of a human colon cancer cell line by introduction of an exogenous NF1 gene. Cancer Res 56:2872–2876

    CAS  PubMed  Google Scholar 

  21. Guo HF, The I, Hannan F, Bernards A, Zhong Y (1997) Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 276:795–798

    CAS  PubMed  Google Scholar 

  22. The I, Hannigan GE, Cowley GS, Reginald S, Zhong Y, Gusella JF, Hariharan IK, Bernards A (1997) Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science 276:791–794

    CAS  PubMed  Google Scholar 

  23. Malhotra R, Ratner N (1994) Localization of neurofibromin to keratinocytes and melanocytes in developing rat and human skin. J Invest Dermatol 102:812–818

    CAS  PubMed  Google Scholar 

  24. Yla-Outinen H, Aaltonen V, Bjorkstrand AS, Hirvonen O, Lakkakorpi J, Vaha-Kreula M, Laato M, Peltonen J (1998) Upregulation of tumor suppressor protein neurofibromin in normal human wound healing and in vitro evidence for platelet derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1) elicited increase in neurofibromin mRNA steady-state levels in dermal fibroblasts. J Invest Dermatol 110:232–237

    CAS  PubMed  Google Scholar 

  25. Koivunen J, Kuorilehto T, Kaisto T, Peltonen S, Peltonen J (2002) Ultrastructural localization of NF1 tumor suppressor protein in human skin. Arch Dermatol Res 293:646–649

    CAS  PubMed  Google Scholar 

  26. Koivunen J, Yla-Outinen H, Korkiamaki T, Karvonen SL, Poyhonen M, Laato M, Karvonen J, Peltonen S, Peltonen J (2000) New function for NF1 tumor suppressor. J Invest Dermatol 114:473–479

    CAS  PubMed  Google Scholar 

  27. Atit RP, Mitchell K, Nguyen L, Warshawsky D, Ratner N (2000) The neurofibromatosis type 1 (Nf1) tumor suppressor is a modifier of carcinogen-induced pigmentation and papilloma formation in C57BL/6 mice. J Invest Dermatol 114:1093–1100

    CAS  PubMed  Google Scholar 

  28. Atit RP, Crowe MJ, Greenhalgh DG, Wenstrup RJ, Ratner N (1999) The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited by fibroblasts. J Invest Dermatol 112:835–842

    CAS  PubMed  Google Scholar 

  29. Friedman JM, Riccardi VM (1999) Neurofibromatosis: phenotype, natural history, and pathogenesis, 3rd edn. Johns Hopkins University Press, Baltimore

    Google Scholar 

  30. Karvonen SL, Kallioinen M, Yla-Outinen H, Poyhonen M, Oikarinen A, Peltonen J (2000) Occult neurofibroma and increased S100 protein in the skin of patients with neurofibromatosis type 1: new insight to the etiopathomechanism of neurofibromas. Arch Dermatol 136:1207–1209

    CAS  PubMed  Google Scholar 

  31. Kiistala U (1968) Suction blister device for separation of viable epidermis from dermis. J Invest Dermatol 50:129–137

    CAS  PubMed  Google Scholar 

  32. Kainulainen T, Hakkinen L, Hamidi S, Larjava K, Kallioinen M, Peltonen J, Salo T, Larjava H, Oikarinen A (1998) Laminin-5 expression is independent of the injury and the microenvironment during reepithelialization of wounds. J Histochem Cytochem 46:353–360

    CAS  PubMed  Google Scholar 

  33. Coulombe PA (1997) Towards a molecular definition of keratinocyte activation after acute injury to stratified epithelia. Biochem Biophys Res Commun 236:231–238

    CAS  PubMed  Google Scholar 

  34. Martin P (1997) Wound healing—aiming for perfect skin regeneration. Science 276:75–81

    CAS  PubMed  Google Scholar 

  35. Pinnagoda J, Tupker RA, Agner T, Serup J (1990) Guidelines for transepidermal water loss (TEWL) measurement. A report from the Standardization Group of the European Society of Contact Dermatitis. Contact Dermatitis 22:164–178

    CAS  PubMed  Google Scholar 

  36. Sawchuk WS, Friedman KJ, Manning T, Pinnell SR (1986) Delayed healing in full-thickness wounds treated with aluminum chloride solution. A histologic study with evaporimetry correlation. J Am Acad Dermatol 15:982–989

    CAS  PubMed  Google Scholar 

  37. Silverman RA, Lender J, Elmets CA (1989) Effects of occlusive and semiocclusive dressings on the return of barrier function to transepidermal water loss in standardized human wounds. J Am Acad Dermatol 20:755–760

    CAS  PubMed  Google Scholar 

  38. Yla-Outinen H, Koivunen J, Nissinen M, Bjorkstrand AS, Paloniemi M, Korkiamaki T, Peltonen S, Karvonen SL, Peltonen J (2002) NF1 tumor suppressor mRNA is targeted to the cell-cell contact zone in Ca(2+)-induced keratinocyte differentiation. Lab Invest 82:353–361

    PubMed  Google Scholar 

  39. Sherman LS, Atit R, Rosenbaum T, Cox AD, Ratner N (2000) Single cell Ras-GTP analysis reveals altered Ras activity in a subpopulation of neurofibroma Schwann cells but not fibroblasts. J Biol Chem 275:30740–30745

    CAS  PubMed  Google Scholar 

  40. Greene JF Jr, Fitzwater JE, Burgess J (1974) Arterial lesions associated with neurofibromatosis. Am J Clin Pathol 62:481–487

    PubMed  Google Scholar 

  41. Lehrnbecher T, Gassel AM, Rauh V, Kirchner T, Huppertz HI (1994) Neurofibromatosis presenting as a severe systemic vasculopathy. Eur J Pediatr 153:107–109

    CAS  PubMed  Google Scholar 

  42. Norton KK, Xu J, Gutmann DH (1995) Expression of the neurofibromatosis I gene product, neurofibromin, in blood vessel endothelial cells and smooth muscle. Neurobiol Dis 2:13–21

    CAS  PubMed  Google Scholar 

  43. Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, Epstein JA (2003) Nf1 has an essential role in endothelial cells. Nat Genet 33:75–79

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Marja Paloniemi for excellent technical assistance. This study was supported by Grants from Cancer Society of Finland, Oulu University Hospital, grant# H01139, Academy of Finland, The Finnish Medical Foundation and Ida Montin Foundation.

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Oulu, Oulu, PB 5000, 90014, Finland

    Jussi Koivunen, Seija-Liisa Karvonen, Heli Ylä-Outinen, Vesa Aaltonen & Juha Peltonen

  2. Department of Dermatology, University of Oulu, Oulu, PB 5000, 90014, Finland

    Seija-Liisa Karvonen, Aarne Oikarinen & Juha Peltonen

  3. Department of Dermatology, Skin and Allergy Hospital, University of Helsinki, Helsinki, PB 160, 00029, Finland

    Seija-Liisa Karvonen

  4. Department of Anatomy, University of Turku, Kiinanmyllynkatu 4-6, 20520, Turku, Finland

    Juha Peltonen

Authors
  1. Jussi Koivunen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seija-Liisa Karvonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heli Ylä-Outinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vesa Aaltonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aarne Oikarinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Juha Peltonen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jussi Koivunen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koivunen, J., Karvonen, SL., Ylä-Outinen, H. et al. NF1 tumor suppressor in epidermal wound healing with special focus on wound healing in patients with type 1 neurofibromatosis. Arch Dermatol Res 296, 547–554 (2005). https://doi.org/10.1007/s00403-005-0564-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-005-0564-x

Keywords

Search

Navigation