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Cell proliferation and oxidative stress pathways are modified in fibroblasts from Sturge–Weber syndrome patients

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Abstract

Sturge–Weber syndrome (SWS) is defined by vascular malformations of the face, eye and brain and an underlying somatic mutation has been hypothesized. We employed isobaric tags for relative and absolute quantification (iTRAQ-8plex)-based liquid chromatography interfaced with tandem mass spectrometry (LC–MS/MS) approach to identify differentially expressed proteins between port-wine-derived and normal skin-derived fibroblasts of four individuals with SWS. Proteins were identified that were significantly up- or down-regulated (i.e., ratios >1.2 or <0.8) in two or three pairs of samples (n = 31/972 quantified proteins) and their associated p values reported. Ingenuity pathway analysis (IPA) tool showed that the up-regulated proteins were associated with pathways that enhance cell proliferation; down-regulated proteins were associated with suppression of cell proliferation. The significant toxicologic list pathway in all four observations was oxidative stress mediated by Nrf2. This proteomics study highlights oxidative stress also consistent with a possible mutation in the RASA1 gene or pathway in SWS.

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References

  1. Aigner L, Arber S, Kapfhammer JP, Laux T, Schneider C, Botteri F, Brenner HR, Caroni P (1995) Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell 83:269–278

    Article  PubMed  CAS  Google Scholar 

  2. Bock KW, Kohle C (2006) Ah receptor: dioxin-mediated toxic responses as hints to deregulated physiologic functions. Biochem Pharmacol 72:393–404

    Article  PubMed  CAS  Google Scholar 

  3. Bodensteiner JB (2001) Sturge–Weber syndrome. Facial Plast Surg Clin North Am 9:569–576

    PubMed  CAS  Google Scholar 

  4. Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L, Lewis CE (2003) Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol 163:1233–1243

    Article  PubMed  CAS  Google Scholar 

  5. Comi AM, Roach ES (2010) Neurologic manifestations of Sturge–Weber syndrome. In: Bodensteiner J, Roach ES (eds) Sturge–Weber syndrome. Sturge–Weber Foundation, Mount Freedom, pp 27–38

    Google Scholar 

  6. Comi AM, Hunt P, Vawter MP, Pardo CA, Becker KG, Pevsner J (2003) Increased fibronectin expression in Sturge–Weber syndrome fibroblasts and brain tissue. Pediatr Res 53:762–769

    Article  PubMed  CAS  Google Scholar 

  7. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, Vanwijck R, Vikkula M (2003) Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73:1240–1249

    Article  PubMed  CAS  Google Scholar 

  8. Elowe S, Holland SJ, Kulkarni S, Pawson T (2001) Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. Mol Cell Biol 21:7429–7441

    Article  PubMed  CAS  Google Scholar 

  9. Hershkovitz D, Bercovich D, Sprecher E, Lapidot M (2008) RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol 158:1035–1040

    Article  PubMed  CAS  Google Scholar 

  10. Hershkovitz D, Bergman R, Sprecher E (2008) A novel mutation in RASA1 causes capillary malformation and limb enlargement. Arch Dermatol Res 300:385–388

    Article  PubMed  CAS  Google Scholar 

  11. Huq AH, Chugani DC, Hukku B, Serajee FJ (2002) Evidence of somatic mosaicism in Sturge–Weber syndrome. Neurology 59:780–782

    PubMed  Google Scholar 

  12. Jardim DL, da Cunha AF, Duarte AS, dos Santos CO, Saad ST, Costa FF (2005) Expression of Sara2 human gene in erythroid progenitors. J Biochem Mol Biol 38:328–333

    Article  PubMed  CAS  Google Scholar 

  13. Kohle C, Bock KW (2007) Coordinate regulation of phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2. Biochem Pharmacol 73:1853–1862

    Article  PubMed  Google Scholar 

  14. Liu J, Chung HJ, Vogt M, Jin Y, Malide D, He L, Dundr M, Levens D (2011) JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. EMBO J 30:846–858

    Article  PubMed  CAS  Google Scholar 

  15. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  16. Miller RS, Ball KL, Comi AM, Germain-Lee EL (2006) Growth hormone deficiency in Sturge–Weber syndrome. Arch Dis Child 91:340–341

    Article  PubMed  CAS  Google Scholar 

  17. Mosevitsky MI (2005) Nerve ending “signal” proteins GAP-43, MARCKS, and BASP1. Int Rev Cytol 245:245–325

    Article  PubMed  CAS  Google Scholar 

  18. Mosevitsky MI, Novitskaya VA, Plekhanov AY, Skladchikova GY (1994) Neuronal protein GAP-43 is a member of novel group of brain acid-soluble proteins (BASPs). Neurosci Res 19:223–228

    Article  PubMed  CAS  Google Scholar 

  19. Ohsawa S, Watanabe T, Katada T, Nishina H, Miura M (2008) Novel antibody to human BASP1 labels apoptotic cells post-caspase activation. Biochem Biophys Res Commun 371:639–643

    Article  PubMed  CAS  Google Scholar 

  20. Park SG, Shin H, Shin YK, Lee Y, Choi EC, Park BJ, Kim S (2005) The novel cytokine p43 stimulates dermal fibroblast proliferation and wound repair. Am J Pathol 166:387–398

    Article  PubMed  CAS  Google Scholar 

  21. Parsa CF (2008) Sturge–Weber syndrome: a unified pathophysiologic mechanism. Curr Treat Options Neurol 10:47–54

    Article  PubMed  Google Scholar 

  22. Poland A, Knutson JC (1982) 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22:517–554

    Article  PubMed  CAS  Google Scholar 

  23. Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Burrows PE, Clapuyt P, Hammer F, Dubois J, Baselga E, Brancati F, Carder R, Quintal JM, Dallapiccola B, Fischer G, Frieden IJ, Garzon M, Harper J, Johnson-Patel J, Labreze C, Martorell L, Paltiel HJ, Pohl A, Prendiville J, Quere I, Siegel DH, Valente EM, Van HA, Van HL, Vaux KK, Vicente A, Weibel L, Chitayat D, Vikkula M (2008) Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat 29:959–965

    Article  PubMed  CAS  Google Scholar 

  24. Shih YP, Liao YC, Lin Y, Lo SH (2010) DLC1 negatively regulates angiogenesis in a paracrine fashion. Cancer Res 70:8270–8275

    Article  PubMed  CAS  Google Scholar 

  25. Smoller BR, Rosen S (1986) Port-wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol 122:177–179

    Article  PubMed  CAS  Google Scholar 

  26. Sujansky E, Conradi S (1995) Sturge–Weber syndrome: age of onset of seizures and glaucoma and the prognosis for affected children. J Child Neurol 10:49–58

    Article  PubMed  CAS  Google Scholar 

  27. Ueda H (2009) Prothymosin [alpha] and cell death mode switch, a novel target for the prevention of cerebral ischemia-induced damage. Pharmacol Ther 123:323–333

    Article  PubMed  CAS  Google Scholar 

  28. Vareli K, Frangou-Lazaridis M (2004) Prothymosin [alpha] is localized in mitotic spindle during mitosis. Biol Cell 96:421–428

    Article  PubMed  CAS  Google Scholar 

  29. Wei BR, Hoover SB, Ross MM, Zhou W, Meani F, Edwards JB, Spehalski EI, Risinger JI, Alvord WG, Quinones OA, Belluco C, Martella L, Campagnutta E, Ravaggi A, Dai RM, Goldsmith PK, Woolard KD, Pecorelli S, Liotta LA, Petricoin EF, Simpson RM (2009) Serum S100A6 concentration predicts peritoneal tumor burden in mice with epithelial ovarian cancer and is associated with advanced stage in patients. PLoS One 4:e7670

    Article  PubMed  Google Scholar 

  30. Yang XY, Guan M, Vigil D, Der CJ, Lowy DR, Popescu NC (2009) p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. Oncogene 28:1401–1409

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We acknowledge grant support from Hunter’s Dream for a Cure and assistance obtaining samples from the Sturge–Weber Foundation and the Maryland Brain Bank. We thank Aditya K. Sreenivasan and Kira Lanier for editing this manuscript, and subjects who donated tissue.

Conflict of interest

The authors do not have a financial relationship with Hunter’s Dream for a Cure Foundation.

Author information

Authors and Affiliations

  1. Departments of Neurology and Developmental Medicine, Hugo Moser Kennedy Krieger Research Institute, Baltimore, USA

    Shilpa D. Kadam & Anne M. Comi

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA

    Shilpa D. Kadam, Paul A. Watkins & Anne M. Comi

  3. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA

    Anne M. Comi

  4. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, USA

    Shilpa D. Kadam

  5. Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, USA

    Marjan Gucek

  6. Institute for Basic Biomedical Sciences, Mass Spectrometry and Proteomics Facility, Johns Hopkins University School of Medicine, Baltimore, USA

    Robert N. Cole

  7. Department of Neurogenetics, Hugo Moser Kennedy Krieger Research Institute, Baltimore, USA

    Paul A. Watkins

Authors
  1. Shilpa D. Kadam
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  2. Marjan Gucek
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  3. Robert N. Cole
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  4. Paul A. Watkins
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  5. Anne M. Comi
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Correspondence to Anne M. Comi.

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Kadam, S.D., Gucek, M., Cole, R.N. et al. Cell proliferation and oxidative stress pathways are modified in fibroblasts from Sturge–Weber syndrome patients. Arch Dermatol Res 304, 229–235 (2012). https://doi.org/10.1007/s00403-012-1210-z

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  • DOI: https://doi.org/10.1007/s00403-012-1210-z

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