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Cell death in the skin

  • Cell Death and Disease
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Abstract

The skin is the largest organ of the body and protects the organism against external physical, chemical and biological insults, such as wounding, ultraviolet radiation and micro-organisms. The epidermis is the upper part of the skin that is continuously renewed. The keratinocytes are the major cell type in the epidermis and undergo a specialized form of programmed cell death, called cornification, which is different from classical apoptosis. In keep with this view, several lines of evidence indicate that NF-kB is an important factor providing protection against keratinocyte apoptosis in homeostatic and inflammatory conditions. In contrast, the hair follicle is an epidermal appendage that shows cyclic apoptosis-driven involution, as part of the normal hair cycle. The different cell death programs need to be well orchestrated to maintain skin homeostasis. One of the major environmental insults to the skin is UVB radiation, causing the occurrence of apoptotic sunburn cells. Deregulation of cell death mechanisms in the skin can lead to diseases such as cancer, necrolysis and graft-versus-host disease. Here we review the apoptotic and the anti-apoptotic mechanisms in skin homeostasis and disease.

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References

  1. Lippens S, Denecker G, Ovaere P, Vandenabeele P, Declercq W (2005) Death penalty for keratinocytes: apoptosis versus cornification. Cell Death Differ 12(Suppl 2):1497–1508. doi:10.1038/sj.cdd.4401722

    Article  PubMed  CAS  Google Scholar 

  2. Lippens S, Kockx M, Knaapen M et al (2000) Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing. Cell Death Differ 7:1218–1224. doi:10.1038/sj.cdd.4400785

    Article  PubMed  CAS  Google Scholar 

  3. Raj D, Brash DE, Grossman D (2006) Keratinocyte apoptosis in epidermal development and disease. J Invest Dermatol 126:243–257. doi:10.1038/sj.jid.5700008

    Article  PubMed  CAS  Google Scholar 

  4. Candi E, Schmidt R, Melino G (2005) The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6:328–340. doi:10.1038/nrm1619

    Article  PubMed  CAS  Google Scholar 

  5. Zeeuwen PL (2004) Epidermal differentiation: the role of proteases and their inhibitors. Eur J Cell Biol 83:761–773. doi:10.1078/0171-9335-00388

    Article  PubMed  CAS  Google Scholar 

  6. Raymond AA, Mechin MC, Nachat R et al (2007) Nine procaspases are expressed in normal human epidermis, but only caspase-14 is fully processed. Br J Dermatol 156:420–427. doi:10.1111/j.1365-2133.2006.07656.x

    Article  PubMed  CAS  Google Scholar 

  7. Okuyama R, Nguyen BC, Talora C et al (2004) High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell 6:551–562. doi:10.1016/S1534-5807(04)00098-X

    Article  PubMed  CAS  Google Scholar 

  8. Fischer H, Rossiter H, Ghannadan M et al (2005) Caspase-14 but not caspase-3 is processed during the development of fetal mouse epidermis. Differentiation 73:406–413

    PubMed  CAS  Google Scholar 

  9. Fischer H, Stichenwirth M, Dockal M et al (2004) Stratum corneum-derived caspase-14 is catalytically active. FEBS Lett 577:446–450. doi:10.1016/j.febslet.2004.10.046

    Article  PubMed  CAS  Google Scholar 

  10. Lippens S, VandenBroecke C, Van Damme E, Tschachler E, Vandenabeele P, Declercq W (2003) Caspase-14 is expressed in the epidermis, the choroid plexus, the retinal pigment epithelium and thymic Hassall’s bodies. Cell Death Differ 10:257–259. doi:10.1038/sj.cdd.4401141

    Article  PubMed  CAS  Google Scholar 

  11. Denecker G, Hoste E, Gilbert B et al (2007) Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 9:666–674. doi:10.1038/ncb1597

    Article  PubMed  CAS  Google Scholar 

  12. Smith FJ, Irvine AD, Terron-Kwiatkowski A et al (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38:337–342. doi:10.1038/ng1743

    Article  PubMed  CAS  Google Scholar 

  13. Rawlings AV, Harding CR (2004) Moisturization and skin barrier function. Dermatol Ther 17(Suppl 1):43–48. doi:10.1111/j.1396-0296.2004.04S1005.x

    Article  PubMed  Google Scholar 

  14. Allombert-Blaise C, Tamiji S, Mortier L et al (2003) Terminal differentiation of human epidermal keratinocytes involves mitochondria- and caspase-dependent cell death pathway. Cell Death Differ 10:850–852. doi:10.1038/sj.cdd.4401245

    Article  PubMed  CAS  Google Scholar 

  15. Chaturvedi V, Qin JZ, Denning MF, Choubey D, Diaz MO, Nickoloff BJ (1999) Apoptosis in proliferating, senescent, and immortalized keratinocytes. J Biol Chem 274:23358–23367. doi:10.1074/jbc.274.33.23358

    Article  PubMed  CAS  Google Scholar 

  16. Qin JZ, Chaturvedi V, Denning MF et al (2002) Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes. Oncogene 21:2991–3002. doi:10.1038/sj.onc.1205404

    Article  PubMed  CAS  Google Scholar 

  17. Grether-Beck S, Felsner I, Brenden H, Krutmann J (2003) Mitochondrial cytochrome c release mediates ceramide-induced activator protein 2 activation and gene expression in keratinocytes. J Biol Chem 278:47498–47507. doi:10.1074/jbc.M309511200

    Article  PubMed  CAS  Google Scholar 

  18. Krajewski S, Krajewska M, Reed JC (1996) Immunohistochemical analysis of in vivo patterns of Bak expression, a proapoptotic member of the Bcl-2 protein family. Cancer Res 56:2849–2855

    PubMed  CAS  Google Scholar 

  19. Krajewski S, Krajewska M, Shabaik A et al (1994) Immunohistochemical analysis of in vivo patterns of Bcl-X expression. Cancer Res 54:5501–5507

    PubMed  CAS  Google Scholar 

  20. Lu QL, Poulsom R, Wong L, Hanby AM (1993) Bcl-2 expression in adult and embryonic non-haematopoietic tissues. J Pathol 169:431–437. doi:10.1002/path.1711690408

    Article  PubMed  CAS  Google Scholar 

  21. Droin NM, Green DR (2004) Role of Bcl-2 family members in immunity and disease. Biochim Biophys Acta 1644:179–188. doi:10.1016/j.bbamcr.2003.10.011

    Article  PubMed  CAS  Google Scholar 

  22. Botchkareva NV, Ahluwalia G, Shander D (2006) Apoptosis in the hair follicle. J Invest Dermatol 126:258–264. doi:10.1038/sj.jid.5700007

    Article  PubMed  CAS  Google Scholar 

  23. Stenn KS, Paus R (2001) Controls of hair follicle cycling. Physiol Rev 81:449–494

    PubMed  CAS  Google Scholar 

  24. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75:229–240. doi:10.1016/0092-8674(93)80065-M

    Article  PubMed  CAS  Google Scholar 

  25. Muller-Rover S, Rossiter H, Paus R et al (2000) Overexpression of Bcl-2 protects from ultraviolet B-induced apoptosis but promotes hair follicle regression and chemotherapy-induced alopecia. Am J Pathol 156:1395–1405

    PubMed  CAS  Google Scholar 

  26. Bouillet P, Cory S, Zhang LC, Strasser A, Adams JM (2001) Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim. Dev Cell 1:645–653. doi:10.1016/S1534-5807(01)00083-1

    Article  PubMed  CAS  Google Scholar 

  27. Ito M, Kawa Y, Ono H et al (1999) Removal of stem cell factor or addition of monoclonal anti-c-KIT antibody induces apoptosis in murine melanocyte precursors. J Invest Dermatol 112:796–801. doi:10.1046/j.1523-1747.1999.00552.x

    Article  PubMed  CAS  Google Scholar 

  28. Botchkarev VA, Botchkareva NV, Albers KM, Chen LH, Welker P, Paus R (2000) A role for p75 neurotrophin receptor in the control of apoptosis-driven hair follicle regression. FASEB J 14:1931–1942. doi:10.1096/fj.99-0930com

    Article  PubMed  CAS  Google Scholar 

  29. Foitzik K, Lindner G, Mueller-Roever S et al (2000) Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo. FASEB J 14:752–760

    PubMed  CAS  Google Scholar 

  30. Peters EM, Hansen MG, Overall RW et al (2005) Control of human hair growth by neurotrophins: brain-derived neurotrophic factor inhibits hair shaft elongation, induces catagen, and stimulates follicular transforming growth factor beta2 expression. J Invest Dermatol 124:675–685. doi:10.1111/j.0022-202X.2005.23648.x

    Article  PubMed  CAS  Google Scholar 

  31. Soma T, Tsuji Y, Hibino T (2002) Involvement of transforming growth factor-beta2 in catagen induction during the human hair cycle. J Invest Dermatol 118:993–997. doi:10.1046/j.1523-1747.2002.01746.x

    Article  PubMed  CAS  Google Scholar 

  32. Tsuji Y, Denda S, Soma T, Raftery L, Momoi T, Hibino T (2003) A potential suppressor of TGF-beta delays catagen progression in hair follicles. J Investig Dermatol Symp Proc 8:65–68. doi:10.1046/j.1523-1747.2003.12173.x

    Article  PubMed  CAS  Google Scholar 

  33. McGowan KM, Tong X, Colucci-Guyon E, Langa F, Babinet C, Coulombe PA (2002) Keratin 17 null mice exhibit age- and strain-dependent alopecia. Genes Dev 16:1412–1422. doi:10.1101/gad.979502

    Article  PubMed  CAS  Google Scholar 

  34. Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A (1999) The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 3:287–296. doi:10.1016/S1097-2765(00)80456-6

    Article  PubMed  CAS  Google Scholar 

  35. Puthalakath H, Villunger A, O’Reilly LA et al (2001) Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science 293:1829–1832

    Article  PubMed  CAS  Google Scholar 

  36. Levy L, Broad S, Diekmann D, Evans RD, Watt FM (2000) Beta1 integrins regulate keratinocyte adhesion and differentiation by distinct mechanisms. Mol Biol Cell 11:453–466

    PubMed  CAS  Google Scholar 

  37. Mitra RS, Wrone-Smith T, Simonian P, Foreman KE, Nunez G, Nickoloff BJ (1997) Apoptosis in keratinocytes is not dependent on induction of differentiation. Lab Invest 76:99–107

    PubMed  CAS  Google Scholar 

  38. Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8:49–62. doi:10.1038/nrm2083

    Article  PubMed  CAS  Google Scholar 

  39. Seitz CS, Lin Q, Deng H, Khavari PA (1998) Alterations in NF-kappaB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kappaB. Proc Natl Acad Sci USA 95:2307–2312. doi:10.1073/pnas.95.5.2307

    Article  PubMed  CAS  Google Scholar 

  40. Rebholz B, Haase I, Eckelt B et al (2007) Crosstalk between keratinocytes and adaptive immune cells in an IkappaBalpha protein-mediated inflammatory disease of the skin. Immunity 27:296–307. doi:10.1016/j.immuni.2007.05.024

    Article  PubMed  CAS  Google Scholar 

  41. Zhang JY, Green CL, Tao S, Khavari PA (2004) NF-kappaB RelA opposes epidermal proliferation driven by TNFR1 and JNK. Genes Dev 18:17–22. doi:10.1101/gad.1160904

    Article  PubMed  CAS  Google Scholar 

  42. Gugasyan R, Voss A, Varigos G et al (2004) The transcription factors c-rel and RelA control epidermal development and homeostasis in embryonic and adult skin via distinct mechanisms. Mol Cell Biol 24:5733–5745. doi:10.1128/MCB.24.13.5733-5745.2004

    Article  PubMed  CAS  Google Scholar 

  43. Seitz CS, Freiberg RA, Hinata K, Khavari PA (2000) NF-kappaB determines localization and features of cell death in epidermis. J Clin Invest 105:253–260. doi:10.1172/JCI7630

    Article  PubMed  CAS  Google Scholar 

  44. Schmidt-Supprian M, Bloch W, Courtois G et al (2000) NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 5:981–992. doi:10.1016/S1097-2765(00)80263-4

    Article  PubMed  CAS  Google Scholar 

  45. Makris C, Godfrey VL, Krahn-Senftleben G et al (2000) Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 5:969–979. doi:10.1016/S1097-2765(00)80262-2

    Article  PubMed  CAS  Google Scholar 

  46. Smahi A, Courtois G, Vabres P et al (2000) Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The international incontinentia pigmenti (IP) consortium. Nature 405:466–472. doi:10.1038/35013114

    Article  PubMed  CAS  Google Scholar 

  47. Omori E, Matsumoto K, Sanjo H et al (2006) TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J Biol Chem 281:19610–19617. doi:10.1074/jbc.M603384200

    Article  PubMed  CAS  Google Scholar 

  48. Sayama K, Hanakawa Y, Nagai H et al (2006) Transforming growth factor-beta-activated kinase 1 is essential for differentiation and the prevention of apoptosis in epidermis. J Biol Chem 281:22013–22020. doi:10.1074/jbc.M601065200

    Article  PubMed  CAS  Google Scholar 

  49. Nenci A, Huth M, Funteh A et al (2006) Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. Hum Mol Genet 15:531–542. doi:10.1093/hmg/ddi470

    Article  PubMed  CAS  Google Scholar 

  50. Pasparakis M, Courtois G, Hafner M et al (2002) TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417:861–866. doi:10.1038/nature00820

    Article  PubMed  CAS  Google Scholar 

  51. Hu Y, Baud V, Delhase M et al (1999) Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 284:316–320

    Article  PubMed  CAS  Google Scholar 

  52. Gareus R, Huth M, Breiden B et al (2007) Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation. Nat Cell Biol 9:461–469. doi:10.1038/ncb1560

    Article  PubMed  CAS  Google Scholar 

  53. Hu Y, Baud V, Oga T, Kim KI, Yoshida K, Karin M (2001) IKKalpha controls formation of the epidermis independently of NF-kappaB. Nature 410:710–714. doi:10.1038/35070605

    Article  PubMed  CAS  Google Scholar 

  54. Klement JF, Rice NR, Car BD et al (1996) IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice. Mol Cell Biol 16:2341–2349

    PubMed  CAS  Google Scholar 

  55. Sayama K, Hanakawa Y, Shirakata Y et al (2001) Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. J Biol Chem 276:999–1004. doi:10.1074/jbc.M003425200

    Article  PubMed  CAS  Google Scholar 

  56. Osaka N, Takahashi T, Murakami S et al (2007) ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds. J Cell Biol 176:903–909. doi:10.1083/jcb.200611015

    Article  PubMed  CAS  Google Scholar 

  57. Sayama K, Komatsuzawa H, Yamasaki K et al (2005) New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of beta-defensins, LL37, and TLR2. Eur J Immunol 35:1886–1895. doi:10.1002/eji.200425827

    Article  PubMed  CAS  Google Scholar 

  58. Wan YS, Wang ZQ, Voorhees J, Fisher G (2001) EGF receptor crosstalks with cytokine receptors leading to the activation of c-Jun kinase in response to UV irradiation in human keratinocytes. Cell Signal 13:139–144. doi:10.1016/S0898-6568(00)00146-7

    Article  PubMed  CAS  Google Scholar 

  59. DiGiovanni J, Bol DK, Wilker E et al (2000) Constitutive expression of insulin-like growth factor-1 in epidermal basal cells of transgenic mice leads to spontaneous tumor promotion. Cancer Res 60:1561–1570

    PubMed  CAS  Google Scholar 

  60. Peng XD, Xu PZ, Chen ML et al (2003) Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev 17:1352–1365. doi:10.1101/gad.1089403

    Article  PubMed  CAS  Google Scholar 

  61. Yang ZZ, Tschopp O, Di-Poi N et al (2005) Dosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice. Mol Cell Biol 25:10407–10418. doi:10.1128/MCB.25.23.10407-10418.2005

    Article  PubMed  CAS  Google Scholar 

  62. Stachelscheid H, Ibrahim H, Koch L et al (2008) Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation. EMBO J 27:2091–2101. doi:10.1038/emboj.2008.141

    Article  PubMed  CAS  Google Scholar 

  63. Thrash BR, Menges CW, Pierce RH, McCance DJ (2006) AKT1 provides an essential survival signal required for differentiation and stratification of primary human keratinocytes. J Biol Chem 281:12155–12162. doi:10.1074/jbc.M512116200

    Article  PubMed  CAS  Google Scholar 

  64. Saegusa J, Hsu DK, Liu W et al (2008) Galectin-3 protects keratinocytes from UVB-induced apoptosis by enhancing AKT activation and suppressing ERK activation. J Invest Dermatol 128:2403–2411. doi:10.1038/jid.2008.119

    Article  PubMed  CAS  Google Scholar 

  65. Larribere L, Khaled M, Tartare-Deckert S et al (2004) PI3K mediates protection against TRAIL-induced apoptosis in primary human melanocytes. Cell Death Differ 11:1084–1091. doi:10.1038/sj.cdd.4401475

    Article  PubMed  CAS  Google Scholar 

  66. Datta SR, Dudek H, Tao X et al (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241. doi:10.1016/S0092-8674(00)80405-5

    Article  PubMed  CAS  Google Scholar 

  67. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85. doi:10.1038/43466

    Article  PubMed  CAS  Google Scholar 

  68. Romashkova JA, Makarov SS (1999) NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90. doi:10.1038/43474

    Article  PubMed  CAS  Google Scholar 

  69. Meng F, Liu L, Chin PC, D’Mello SR (2002) Akt is a downstream target of NF-kappa B. J Biol Chem 277:29674–29680. doi:10.1074/jbc.M112464200

    Article  PubMed  CAS  Google Scholar 

  70. Rygiel TP, Mertens AE, Strumane K, van der Kammen R, Collard JG (2008) The Rac activator Tiam1 prevents keratinocyte apoptosis by controlling ROS-mediated ERK phosphorylation. J Cell Sci 121:1183–1192. doi:10.1242/jcs.017194

    Article  PubMed  CAS  Google Scholar 

  71. Bokoch GM (2003) Biology of the p21-activated kinases. Annu Rev Biochem 72:743–781. doi:10.1146/annurev.biochem.72.121801.161742

    Article  PubMed  CAS  Google Scholar 

  72. Jin S, Zhuo Y, Guo W, Field J (2005) p21-activated Kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association. J Biol Chem 280:24698–24705. doi:10.1074/jbc.M413374200

    Article  PubMed  CAS  Google Scholar 

  73. Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501. doi:10.1016/S0092-8674(01)00237-9

    Article  PubMed  CAS  Google Scholar 

  74. Viard-Leveugle I, Bullani RR, Meda P et al (2003) Intracellular localization of keratinocyte Fas ligand explains lack of cytolytic activity under physiological conditions. J Biol Chem 278:16183–16188. doi:10.1074/jbc.M212188200

    Article  PubMed  CAS  Google Scholar 

  75. Bayes M, Hartung AJ, Ezer S et al (1998) The anhidrotic ectodermal dysplasia gene (EDA) undergoes alternative splicing and encodes ectodysplasin—a with deletion mutations in collagenous repeats. Hum Mol Genet 7:1661–1669. doi:10.1093/hmg/7.11.1661

    Article  PubMed  CAS  Google Scholar 

  76. Bossen C, Ingold K, Tardivel A et al (2006) Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J Biol Chem 281:13964–13971. doi:10.1074/jbc.M601553200

    Article  PubMed  CAS  Google Scholar 

  77. Yan M, Wang LC, Hymowitz SG et al (2000) Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors. Science 290:523–527

    Article  PubMed  CAS  Google Scholar 

  78. Headon DJ, Overbeek PA (1999) Involvement of a novel Tnf receptor homologue in hair follicle induction. Nat Genet 22:370–374. doi:10.1038/11943

    Article  PubMed  CAS  Google Scholar 

  79. Srivastava AK, Pispa J, Hartung AJ et al (1997) The tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains. Proc Natl Acad Sci USA 94:13069–13074. doi:10.1073/pnas.94.24.13069

    Article  PubMed  CAS  Google Scholar 

  80. Ferguson BM, Brockdorff N, Formstone E, Ngyuen T, Kronmiller JE, Zonana J (1997) Cloning of tabby, the murine homolog of the human EDA gene: evidence for a membrane-associated protein with a short collagenous domain. Hum Mol Genet 6:1589–1594. doi:10.1093/hmg/6.9.1589

    Article  PubMed  CAS  Google Scholar 

  81. Ohazama A, Courtney JM, Tucker AS et al (2004) Traf6 is essential for murine tooth cusp morphogenesis. Dev Dyn 229:131–135. doi:10.1002/dvdy.10400

    Article  PubMed  CAS  Google Scholar 

  82. Headon DJ, Emmal SA, Ferguson BM et al (2001) Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature 414:913–916. doi:10.1038/414913a

    Article  PubMed  CAS  Google Scholar 

  83. Yan M, Zhang Z, Brady JR, Schilbach S, Fairbrother WJ, Dixit VM (2002) Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice. Curr Biol 12:409–413. doi:10.1016/S0960-9822(02)00687-5

    Article  PubMed  CAS  Google Scholar 

  84. Naito A, Yoshida H, Nishioka E et al (2002) TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci USA 99:8766–8771

    PubMed  CAS  Google Scholar 

  85. Fessing MY, Sharova TY, Sharov AA, Atoyan R, Botchkarev VA (2006) Involvement of the Edar signaling in the control of hair follicle involution (catagen). Am J Pathol 169:2075–2084. doi:10.2353/ajpath.2006.060227

    Article  PubMed  CAS  Google Scholar 

  86. Schneider P, Street SL, Gaide O et al (2001) Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A. J Biol Chem 276:18819–18827. doi:10.1074/jbc.M101280200

    Article  PubMed  CAS  Google Scholar 

  87. Srivastava AK, Durmowicz MC, Hartung AJ et al (2001) Ectodysplasin-A1 is sufficient to rescue both hair growth and sweat glands in tabby mice. Hum Mol Genet 10:2973–2981. doi:10.1093/hmg/10.26.2973

    Article  PubMed  CAS  Google Scholar 

  88. Gaide O, Schneider P (2003) Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nat Med 9:614–618. doi:10.1038/nm861

    Article  PubMed  CAS  Google Scholar 

  89. Casal ML, Lewis JR, Mauldin EA et al (2007) Significant correction of disease after postnatal administration of recombinant ectodysplasin A in canine X-linked ectodermal dysplasia. Am J Hum Genet 81:1050–1056. doi:10.1086/521988

    Article  PubMed  CAS  Google Scholar 

  90. Greenlee RT, Hill-Harmon MB, Murray T, Thun M (2001) Cancer statistics, 2001. CA Cancer J Clin 51:15–36

    Article  PubMed  CAS  Google Scholar 

  91. Matsunaga T, Hieda K, Nikaido O (1991) Wavelength dependent formation of thymine dimers and (6–4) photoproducts in DNA by monochromatic ultraviolet light ranging from 150 to 365 nm. Photochem Photobiol 54:403–410. doi:10.1111/j.1751-1097.1991.tb02034.x

    Article  PubMed  CAS  Google Scholar 

  92. Marchese C, Maresca V, Cardinali G et al (2003) UVB-induced activation and internalization of keratinocyte growth factor receptor. Oncogene 22:2422–2431. doi:10.1038/sj.onc.1206301

    Article  PubMed  CAS  Google Scholar 

  93. Sancar A (1995) DNA repair in humans. Annu Rev Genet 29:69–105. doi:10.1146/annurev.ge.29.120195.000441

    Article  PubMed  CAS  Google Scholar 

  94. Daniels F Jr, Brophy D, Lobitz WC Jr (1961) Histochemical responses of human skin following ultraviolet irradiation. J Invest Dermatol 37:351–357

    PubMed  CAS  Google Scholar 

  95. Efeyan A, Serrano M (2007) p53: guardian of the genome and policeman of the oncogenes. Cell Cycle 6:1006–1010

    PubMed  CAS  Google Scholar 

  96. Balint EE, Vousden KH (2001) Activation and activities of the p53 tumour suppressor protein. Br J Cancer 85:1813–1823. doi:10.1054/bjoc.2001.2128

    Article  CAS  Google Scholar 

  97. Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283. doi:10.1038/nrm2147

    Article  PubMed  CAS  Google Scholar 

  98. Ehrhart JC, Gosselet FP, Culerrier RM, Sarasin A (2003) UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis. Photochem Photobiol Sci 2:825–834. doi:10.1039/b302281a

    Article  PubMed  CAS  Google Scholar 

  99. Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev 3:155–168

    CAS  Google Scholar 

  100. Ziegler A, Jonason AS, Leffell DJ et al (1994) Sunburn and p53 in the onset of skin cancer. Nature 372:773–776. doi:10.1038/372773a0

    Article  PubMed  CAS  Google Scholar 

  101. Bruins W, Zwart E, Attardi LD et al (2004) Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389. Mol Cell Biol 24:8884–8894. doi:10.1128/MCB.24.20.8884-8894.2004

    Article  PubMed  CAS  Google Scholar 

  102. Caelles C, Helmberg A, Karin M (1994) p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 370:220–223. doi:10.1038/370220a0

    Article  PubMed  CAS  Google Scholar 

  103. Wagner AJ, Kokontis JM, Hay N (1994) Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev 8:2817–2830. doi:10.1101/gad.8.23.2817

    Article  PubMed  CAS  Google Scholar 

  104. Erster S, Moll UM (2005) Stress-induced p53 runs a transcription-independent death program. Biochem Biophys Res Commun 331:843–850. doi:10.1016/j.bbrc.2005.03.187

    Article  PubMed  CAS  Google Scholar 

  105. Thornborrow EC, Patel S, Mastropietro AE, Schwartzfarb EM, Manfredi JJ (2002) A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene 21:990–999. doi:10.1038/sj.onc.1205069

    Article  PubMed  CAS  Google Scholar 

  106. Mathai JP, Germain M, Marcellus RC, Shore GC (2002) Induction and endoplasmic reticulum location of BIK/NBK in response to apoptotic signaling by E1A and p53. Oncogene 21:2534–2544. doi:10.1038/sj.onc.1205340

    Article  PubMed  CAS  Google Scholar 

  107. Zilfou JT, Spector MS, Lowe SW (2005) Slugging it out: fine tuning the p53-PUMA death connection. Cell 123:545–548. doi:10.1016/j.cell.2005.11.003

    Article  PubMed  CAS  Google Scholar 

  108. Naik E, Michalak EM, Villunger A, Adams JM, Strasser A (2007) Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. J Cell Biol 176:415–424. doi:10.1083/jcb.200608070

    Article  PubMed  CAS  Google Scholar 

  109. Lakhani SA, Masud A, Kuida K et al (2006) Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311:847–851

    Article  PubMed  CAS  Google Scholar 

  110. Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM (2005) The antioxidant function of the p53 tumor suppressor. Nat Med 11:1306–1313. doi:10.1038/nm1320

    Article  PubMed  CAS  Google Scholar 

  111. Cui R, Widlund HR, Feige E et al (2007) Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 128:853–864. doi:10.1016/j.cell.2006.12.045

    Article  PubMed  CAS  Google Scholar 

  112. Hsieh JK, Yap D, O’Connor DJ et al (2002) Novel function of the cyclin A binding site of E2F in regulating p53-induced apoptosis in response to DNA damage. Mol Cell Biol 22:78–93. doi:10.1128/MCB.22.1.78-93.2002

    Article  PubMed  CAS  Google Scholar 

  113. Nahle Z, Polakoff J, Davuluri RV et al (2002) Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol 4:859–864. doi:10.1038/ncb868

    Article  PubMed  CAS  Google Scholar 

  114. Berton TR, Mitchell DL, Guo R, Johnson DG (2005) Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation. Oncogene 24:2449–2460. doi:10.1038/sj.onc.1208462

    Article  PubMed  CAS  Google Scholar 

  115. Wikonkal NM, Remenyik E, Knezevic D et al (2003) Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice. Nat Cell Biol 5:655–660. doi:10.1038/ncb1001

    Article  PubMed  CAS  Google Scholar 

  116. Rodier F, Campisi J, Bhaumik D (2007) Two faces of p53: aging and tumor suppression. Nucleic Acids Res 35:7475–7484. doi:10.1093/nar/gkm744

    Article  PubMed  CAS  Google Scholar 

  117. Yang A, Schweitzer R, Sun D et al (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398:714–718. doi:10.1038/19539

    Article  PubMed  CAS  Google Scholar 

  118. Ferguson-Yates BE, Li H, Dong TK, Hsiao JL, Oh DH (2008) Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63. Carcinogenesis 29:70–75. doi:10.1093/carcin/bgm244

    Article  PubMed  CAS  Google Scholar 

  119. Yang A, Walker N, Bronson R et al (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404:99–103. doi:10.1038/35003607

    Article  PubMed  CAS  Google Scholar 

  120. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A (1999) p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398:708–713. doi:10.1038/19531

    Article  PubMed  CAS  Google Scholar 

  121. Yang A, Kaghad M, Wang Y et al (1998) p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2:305–316. doi:10.1016/S1097-2765(00)80275-0

    Article  PubMed  CAS  Google Scholar 

  122. Candi E, Cipollone R, Rivetti di Val Cervo P, Gonfloni S, Melino G, Knight R (2008) p63 in epithelial development. Cell Mol Life Sci 65:3126–3133

    Google Scholar 

  123. Nylander K, Coates PJ, Hall PA (2000) Characterization of the expression pattern of p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions. Int J Cancer 87:368–372. doi:10.1002/1097-0215(20000801)87:3<368::AID-IJC9>3.0.CO;2-J

    Article  PubMed  CAS  Google Scholar 

  124. Papoutsaki M, Moretti F, Lanza M et al (2005) A p38-dependent pathway regulates DeltaNp63 DNA binding to p53-dependent promoters in UV-induced apoptosis of keratinocytes. Oncogene 24:6970–6975. doi:10.1038/sj.onc.1208835

    Article  PubMed  CAS  Google Scholar 

  125. Bulavin DV, Saito S, Hollander MC et al (1999) Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J 18:6845–6854. doi:10.1093/emboj/18.23.6845

    Article  PubMed  CAS  Google Scholar 

  126. Hildesheim J, Bulavin DV, Anver MR et al (2002) Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res 62:7305–7315

    PubMed  CAS  Google Scholar 

  127. Assefa Z, Van Laethem A, Garmyn M, Agostinis P (2005) Ultraviolet radiation-induced apoptosis in keratinocytes: on the role of cytosolic factors. Biochim Biophys Acta 1755:90–106

    PubMed  CAS  Google Scholar 

  128. Knezevic D, Zhang W, Rochette PJ, Brash DE (2007) Bcl-2 is the target of a UV-inducible apoptosis switch and a node for UV signaling. Proc Natl Acad Sci USA 104:11286–11291. doi:10.1073/pnas.0701318104

    Article  PubMed  CAS  Google Scholar 

  129. Chaturvedi V, Qin JZ, Stennett L, Choubey D, Nickoloff BJ (2004) Resistance to UV-induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53. J Cell Physiol 198:100–109. doi:10.1002/jcp.10392

    Article  PubMed  CAS  Google Scholar 

  130. Mandinova A, Lefort K, Tommasi di Vignano A et al (2008) The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response. EMBO J 27:1243–1254. doi:10.1038/emboj.2008.45

    Article  PubMed  CAS  Google Scholar 

  131. Contassot E, Gaide O, French LE (2007) Death receptors and apoptosis. Dermatol Clin 25:487–501. doi:10.1016/j.det.2007.06.010 vii

    PubMed  CAS  Google Scholar 

  132. Takahashi H, Ishida-Yamamoto A (2001) Iizuka H Ultraviolet B irradiation induces apoptosis of keratinocytes by direct activation of Fas antigen. J Investig Dermatol Symp Proc 6:64–68

    Article  PubMed  CAS  Google Scholar 

  133. Schwarz A, Bhardwaj R, Aragane Y et al (1995) Ultraviolet-B-induced apoptosis of keratinocytes: evidence for partial involvement of tumor necrosis factor-alpha in the formation of sunburn cells. J Invest Dermatol 104:922–927. doi:10.1111/1523-1747.ep12606202

    Article  PubMed  CAS  Google Scholar 

  134. Aragane Y, Kulms D, Metze D et al (1998) Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. J Cell Biol 140:171–182. doi:10.1083/jcb.140.1.171

    Article  PubMed  CAS  Google Scholar 

  135. Maeda T, Hao C, Tron VA (2001) Ultraviolet light (UV) regulation of the TNF family decoy receptors DcR2 and DcR3 in human keratinocytes. J Cutan Med Surg 5:294–298. doi:10.1007/s102270000030

    PubMed  CAS  Google Scholar 

  136. Hill LL, Shreedhar VK, Kripke ML, Owen-Schaub LB (1999) A critical role for Fas ligand in the active suppression of systemic immune responses by ultraviolet radiation. J Exp Med 189:1285–1294. doi:10.1084/jem.189.8.1285

    Article  PubMed  CAS  Google Scholar 

  137. Zhuang L, Wang B, Shinder GA, Shivji GM, Mak TW, Sauder DN (1999) TNF receptor p55 plays a pivotal role in murine keratinocyte apoptosis induced by ultraviolet B irradiation. J Immunol 162:1440–1447

    PubMed  CAS  Google Scholar 

  138. Sitailo LA, Tibudan SS, Denning MF (2002) Activation of caspase-9 is required for UV-induced apoptosis of human keratinocytes. J Biol Chem 277:19346–19352. doi:10.1074/jbc.M200401200

    Article  PubMed  CAS  Google Scholar 

  139. Grossman D, Kim PJ, Blanc-Brude OP et al (2001) Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J Clin Invest 108:991–999

    PubMed  CAS  Google Scholar 

  140. Takahashi H, Honma M, Ishida-Yamamoto A et al (2001) In vitro and in vivo transfer of bcl-2 gene into keratinocytes suppresses UVB-induced apoptosis. Photochem Photobiol 74:579–586. doi:10.1562/0031-8655(2001)074<0579:IVAIVT>2.0.CO;2

    Article  PubMed  CAS  Google Scholar 

  141. Assefa Z, Garmyn M, Vantieghem A et al (2003) Ultraviolet B radiation-induced apoptosis in human keratinocytes: cytosolic activation of procaspase-8 and the role of Bcl-2. FEBS Lett 540:125–132. doi:10.1016/S0014-5793(03)00238-2

    Article  PubMed  CAS  Google Scholar 

  142. Nickoloff BJ, Qin JZ, Chaturvedi V, Bacon P, Panella J, Denning MF (2002) Life and death signaling pathways contributing to skin cancer. J Investig Dermatol Symp Proc 7:27–35. doi:10.1046/j.1523-1747.2002.19633.x

    Article  PubMed  CAS  Google Scholar 

  143. Denning MF, Wang Y, Nickoloff BJ, Wrone-Smith T (1998) Protein kinase Cdelta is activated by caspase-dependent proteolysis during ultraviolet radiation-induced apoptosis of human keratinocytes. J Biol Chem 273:29995–30002. doi:10.1074/jbc.273.45.29995

    Article  PubMed  CAS  Google Scholar 

  144. D’Costa AM, Denning MF (2005) A caspase-resistant mutant of PKC-delta protects keratinocytes from UV-induced apoptosis. Cell Death Differ 12:224–232. doi:10.1038/sj.cdd.4401558

    Article  PubMed  CAS  Google Scholar 

  145. Sitailo LA, Tibudan SS, Denning MF (2004) Bax activation and induction of apoptosis in human keratinocytes by the protein kinase C delta catalytic domain. J Invest Dermatol 123:434–443. doi:10.1111/j.0022-202X.2004.23403.x

    Article  PubMed  CAS  Google Scholar 

  146. Sitailo LA, Tibudan SS, Denning MF (2006) The protein kinase C delta catalytic fragment targets Mcl-1 for degradation to trigger apoptosis. J Biol Chem 281:29703–29710. doi:10.1074/jbc.M607351200

    Article  PubMed  CAS  Google Scholar 

  147. Van Laethem A, Van Kelst S, Lippens S et al (2004) Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB J 18:1946–1948

    PubMed  Google Scholar 

  148. Bickers DR, Athar M (2006) Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 126:2565–2575. doi:10.1038/sj.jid.5700340

    Article  PubMed  CAS  Google Scholar 

  149. Bode AM, Dong Z (2003) Mitogen-activated protein kinase activation in UV-induced signal transduction. Sci STKE 2003(167):RE2

    Article  PubMed  Google Scholar 

  150. Gross S, Knebel A, Tenev T et al (1999) Inactivation of protein-tyrosine phosphatases as mechanism of UV-induced signal transduction. J Biol Chem 274:26378–26386. doi:10.1074/jbc.274.37.26378

    Article  PubMed  CAS  Google Scholar 

  151. Gulati P, Markova B, Gottlicher M, Bohmer FD, Herrlich PA (2004) UVA inactivates protein tyrosine phosphatases by calpain-mediated degradation. EMBO Rep 5:812–817. doi:10.1038/sj.embor.7400190

    Article  PubMed  CAS  Google Scholar 

  152. Wang H, Kochevar IE (2005) Involvement of UVB-induced reactive oxygen species in TGF-beta biosynthesis and activation in keratinocytes. Free Radic Biol Med 38:890–897. doi:10.1016/j.freeradbiomed.2004.12.005

    Article  PubMed  CAS  Google Scholar 

  153. Van Laethem A, Nys K, Van Kelst S et al (2006) Apoptosis signal regulating kinase-1 connects reactive oxygen species to p38 MAPK-induced mitochondrial apoptosis in UVB-irradiated human keratinocytes. Free Radic Biol Med 41:1361–1371. doi:10.1016/j.freeradbiomed.2006.07.007

    Article  PubMed  CAS  Google Scholar 

  154. Qin JZ, Chaturvedi V, Denning MF, Choubey D, Diaz MO, Nickoloff BJ (1999) Role of NF-kappaB in the apoptotic-resistant phenotype of keratinocytes. J Biol Chem 274:37957–37964. doi:10.1074/jbc.274.53.37957

    Article  PubMed  CAS  Google Scholar 

  155. van Hogerlinden M, Rozell BL, Ahrlund-Richter L, Toftgard R (1999) Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res 59:3299–3303

    PubMed  Google Scholar 

  156. Herrlich P, Karin M, Weiss C (2008) Supreme EnLIGHTenment: damage recognition and signaling in the mammalian UV response. Mol Cell 29:279–290. doi:10.1016/j.molcel.2008.01.001

    Article  PubMed  CAS  Google Scholar 

  157. Lewis DA, Spandau DF (2008) UVB-induced activation of NF-kappaB is regulated by the IGF-1R and dependent on p38 MAPK. J Invest Dermatol 128:1022–1029. doi:10.1038/sj.jid.5701127

    Article  PubMed  CAS  Google Scholar 

  158. Claerhout S, Decraene D, Van Laethem A, Van Kelst S, Agostinis P, Garmyn M (2007) AKT delays the early-activated apoptotic pathway in UVB-irradiated keratinocytes via BAD translocation. J Invest Dermatol 127:429–438. doi:10.1038/sj.jid.5700533

    Article  PubMed  CAS  Google Scholar 

  159. Fritsche E, Schafer C, Calles C et al (2007) Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci USA 104:8851–8856. doi:10.1073/pnas.0701764104

    Article  PubMed  CAS  Google Scholar 

  160. Akunda JK, Chun KS, Sessoms AR, Lao HC, Fischer SM, Langenbach R (2007) Cyclooxygenase-2 deficiency increases epidermal apoptosis and impairs recovery following acute UVB exposure. Mol Carcinog 46:354–362. doi:10.1002/mc.20290

    Article  PubMed  CAS  Google Scholar 

  161. Chun KS, Akunda JK, Langenbach R (2007) Cyclooxygenase-2 inhibits UVB-induced apoptosis in mouse skin by activating the prostaglandin E2 receptors, EP2 and EP4. Cancer Res 67:2015–2021. doi:10.1158/0008-5472.CAN-06-3617

    Article  PubMed  CAS  Google Scholar 

  162. Fischer SM, Pavone A, Mikulec C, Langenbach R, Rundhaug JE (2007) Cyclooxygenase-2 expression is critical for chronic UV-induced murine skin carcinogenesis. Mol Carcinog 46:363–371. doi:10.1002/mc.20284

    Article  PubMed  CAS  Google Scholar 

  163. Fukuda I, Mukai R, Kawase M, Yoshida K, Ashida H (2007) Interaction between the aryl hydrocarbon receptor and its antagonists, flavonoids. Biochem Biophys Res Commun 359:822–827. doi:10.1016/j.bbrc.2007.05.199

    Article  PubMed  CAS  Google Scholar 

  164. Ellison TI, Smith MK, Gilliam AC, MacDonald PN (2008) Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis. J Invest Dermatol 128:2508–2517. doi:10.1038/jid.2008.131

    Article  PubMed  CAS  Google Scholar 

  165. Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S, Beer HD (2007) The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes. Curr Biol 17:1140–1145. doi:10.1016/j.cub.2007.05.074

    Article  PubMed  CAS  Google Scholar 

  166. Faustin B, Reed JC (2008) Sunburned skin activates inflammasomes. Trends Cell Biol 18:4–8. doi:10.1016/j.tcb.2007.10.004

    Article  PubMed  CAS  Google Scholar 

  167. Nakagaki T, Oda J, Koizumi H, Fukaya T, Yasui C, Ueda T (1990) Ultraviolet action spectrum for intracellular free Ca2+ increase in human epidermal keratinocytes. Cell Struct Funct 15:175–179

    Article  PubMed  CAS  Google Scholar 

  168. Gibbs NK, Tye J, Norval M (2008) Recent advances in urocanic acid photochemistry, photobiology and photoimmunology. Photochem Photobiol Sci 7:655–667. doi:10.1039/b717398a

    Article  PubMed  CAS  Google Scholar 

  169. Denecker G, Ovaere P, Vandenabeele P, Declercq W (2008) Caspase-14 reveals its secrets. J Cell Biol 180:451–458. doi:10.1083/jcb.200709098

    Article  PubMed  CAS  Google Scholar 

  170. Eckhart L, Ballaun C, Hermann M et al (2008) Identification of novel mammalian caspases reveals an important role of gene loss in shaping the human caspase repertoire. Mol Biol Evol 25:831–841. doi:10.1093/molbev/msn012

    Article  PubMed  CAS  Google Scholar 

  171. Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev 5:876–885

    CAS  Google Scholar 

  172. Brash DE, Rudolph JA, Simon JA et al (1991) A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 88:10124–10128. doi:10.1073/pnas.88.22.10124

    Article  PubMed  CAS  Google Scholar 

  173. Lacour JP (2002) Carcinogenesis of basal cell carcinomas: genetics and molecular mechanisms. Br J Dermatol 146(Suppl 61):17–19. doi:10.1046/j.1365-2133.146.s61.5.x

    Article  PubMed  CAS  Google Scholar 

  174. Jiang W, Ananthaswamy HN, Muller HK, Kripke ML (1999) p53 protects against skin cancer induction by UV-B radiation. Oncogene 18:4247–4253. doi:10.1038/sj.onc.1202789

    Article  PubMed  CAS  Google Scholar 

  175. Li G, Tron V, Ho V (1998) Induction of squamous cell carcinoma in p53-deficient mice after ultraviolet irradiation. J Invest Dermatol 110:72–75. doi:10.1046/j.1523-1747.1998.00090.x

    Article  PubMed  CAS  Google Scholar 

  176. Ganguli G, Abecassis J, Wasylyk B (2000) MDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis. EMBO J 19:5135–5147. doi:10.1093/emboj/19.19.5135

    Article  PubMed  CAS  Google Scholar 

  177. Ball NJ, Yohn JJ, Morelli JG, Norris DA, Golitz LE, Hoeffler JP (1994) Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol 102:285–290. doi:10.1111/1523-1747.ep12371783

    Article  PubMed  CAS  Google Scholar 

  178. Hahne M, Rimoldi D, Schroter M et al (1996) Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363–1366

    Article  PubMed  CAS  Google Scholar 

  179. Jafari M, Papp T, Kirchner S et al (1995) Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma. J Cancer Res Clin Oncol 121:23–30. doi:10.1007/BF01202725

    Article  PubMed  CAS  Google Scholar 

  180. Sprecher E, Bergman R, Meilick A et al (1999) Apoptosis, Fas and Fas-ligand expression in melanocytic tumors. J Cutan Pathol 26:72–77. doi:10.1111/j.1600-0560.1999.tb01805.x

    Article  PubMed  CAS  Google Scholar 

  181. Wagner SN, Ockenfels HM, Wagner C, Hofler H, Goos M (1995) Ras gene mutations: a rare event in nonmetastatic primary malignant melanoma. J Invest Dermatol 104:868–871. doi:10.1111/1523-1747.ep12607039

    Article  PubMed  CAS  Google Scholar 

  182. Shin MS, Park WS, Kim SY et al (1999) Alterations of Fas (Apo-1/CD95) gene in cutaneous malignant melanoma. Am J Pathol 154:1785–1791

    PubMed  CAS  Google Scholar 

  183. Buechner SA, Wernli M, Harr T, Hahn S, Itin P, Erb P (1997) Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide. J Clin Invest 100:2691–2696. doi:10.1172/JCI119814

    Article  PubMed  CAS  Google Scholar 

  184. Moers C, Warskulat U, Muschen M et al (1999) Regulation of CD95 (Apo-1/Fas) ligand and receptor expression in squamous-cell carcinoma by interferon-gamma and cisplatin. Int J Cancer 80:564–572. doi:10.1002/(SICI)1097-0215(19990209)80:4<564::AID-IJC14>3.0.CO;2-X

    Article  PubMed  CAS  Google Scholar 

  185. Humphreys RC, Halpern W (2008) TRAIL receptors: targets for cancer therapy. Adv Exp Med Biol 615:127–158. doi:10.1007/978-1-4020-6554-5_7

    Article  PubMed  Google Scholar 

  186. Kruyt FA (2008) TRAIL and cancer therapy. Cancer Lett 263:14–25. doi:10.1016/j.canlet.2008.02.003

    Article  PubMed  CAS  Google Scholar 

  187. Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ (1998) Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol 161:2833–2840

    PubMed  CAS  Google Scholar 

  188. Griffith TS, Lynch DH (1998) TRAIL: a molecule with multiple receptors and control mechanisms. Curr Opin Immunol 10:559–563. doi:10.1016/S0952-7915(98)80224-0

    Article  PubMed  CAS  Google Scholar 

  189. Thomas WD, Hersey P (1998) TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol 161:2195–2200

    PubMed  CAS  Google Scholar 

  190. Djerbi M, Screpanti V, Catrina AI, Bogen B, Biberfeld P, Grandien A (1999) The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med 190:1025–1032. doi:10.1084/jem.190.7.1025

    Article  PubMed  CAS  Google Scholar 

  191. Medema JP, de Jong J, van Hall T, Melief CJ, Offringa R (1999) Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein. J Exp Med 190:1033–1038. doi:10.1084/jem.190.7.1033

    Article  PubMed  CAS  Google Scholar 

  192. Bowen AR, Hanks AN, Murphy KJ, Florell SR, Grossman D (2004) Proliferation, apoptosis, and survivin expression in keratinocytic neoplasms and hyperplasias. Am J Dermatopathol 26:177–181. doi:10.1097/00000372-200406000-00001

    Article  PubMed  Google Scholar 

  193. Pena JC, Rudin CM, Thompson CBA (1998) Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas. Cancer Res 58:2111–2116

    PubMed  CAS  Google Scholar 

  194. Rodriguez-Villanueva J, Greenhalgh D, Wang XJ et al (1998) Human keratin-1.bcl-2 transgenic mice aberrantly express keratin 6, exhibit reduced sensitivity to keratinocyte cell death induction, and are susceptible to skin tumor formation. Oncogene 16:853–863. doi:10.1038/sj.onc.1201610

    Article  PubMed  CAS  Google Scholar 

  195. Chawla-Sarkar M, Bae SI, Reu FJ, Jacobs BS, Lindner DJ, Borden EC (2004) Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ 11:915–923. doi:10.1038/sj.cdd.4401416

    Article  PubMed  CAS  Google Scholar 

  196. Klasa RJ, Gillum AM, Klem RE, Frankel SR (2002) Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 12:193–213. doi:10.1089/108729002760220798

    Article  PubMed  CAS  Google Scholar 

  197. Cummings J, Ward TH, Ranson M, Dive C (2004) Apoptosis pathway-targeted drugs—from the bench to the clinic. Biochim Biophys Acta 1705:53–66

    PubMed  CAS  Google Scholar 

  198. Gleave ME, Monia BP (2005) Antisense therapy for cancer. Nat Rev 5:468–479

    CAS  Google Scholar 

  199. Zhang L, Ming L, Yu J (2007) BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist Updat 10:207–217. doi:10.1016/j.drup.2007.08.002

    Article  PubMed  CAS  Google Scholar 

  200. Fulda S, Debatin KM (2006) Targeting inhibitor of apoptosis proteins (IAPs) for diagnosis and treatment of human diseases. Recent Pat Anticancer Drug Discov 1:81–89. doi:10.2174/157489206775246539

    Article  PubMed  CAS  Google Scholar 

  201. Hafner C, Lopez-Knowles E, Luis NM et al (2007) Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc Natl Acad Sci USA 104:13450–13454. doi:10.1073/pnas.0705218104

    Article  PubMed  CAS  Google Scholar 

  202. Segrelles C, Lu J, Hammann B et al (2007) Deregulated activity of Akt in epithelial basal cells induces spontaneous tumors and heightened sensitivity to skin carcinogenesis. Cancer Res 67:10879–10888. doi:10.1158/0008-5472.CAN-07-2564

    Article  PubMed  CAS  Google Scholar 

  203. Segrelles C, Ruiz S, Perez P et al (2002) Functional roles of Akt signaling in mouse skin tumorigenesis. Oncogene 21:53–64. doi:10.1038/sj.onc.1205032

    Article  PubMed  CAS  Google Scholar 

  204. Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev 3:859–868

    Article  CAS  Google Scholar 

  205. Zenz R, Wagner EF (2006) Jun signalling in the epidermis: from developmental defects to psoriasis and skin tumors. Int J Biochem Cell Biol 38:1043–1049. doi:10.1016/j.biocel.2005.11.011

    Article  PubMed  CAS  Google Scholar 

  206. Yamamoto Y, Gaynor RB (2001) Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 107:135–142. doi:10.1172/JCI11914

    Article  PubMed  CAS  Google Scholar 

  207. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R (2003) Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424:797–801. doi:10.1038/nature01811

    Article  PubMed  CAS  Google Scholar 

  208. Massoumi R, Podda M, Fassler R, Paus R (2006) Cylindroma as tumor of hair follicle origin. J Invest Dermatol 126:1182–1184. doi:10.1038/sj.jid.5700218

    Article  PubMed  CAS  Google Scholar 

  209. Regamey A, Hohl D, Liu JW et al (2003) The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. J Exp Med 198:1959–1964. doi:10.1084/jem.20031187

    Article  PubMed  CAS  Google Scholar 

  210. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G (2003) CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424:793–796. doi:10.1038/nature01803

    Article  PubMed  CAS  Google Scholar 

  211. Khavari PA (2006) Modelling cancer in human skin tissue. Nat Rev 6:270–280

    CAS  Google Scholar 

  212. Dajee M, Lazarov M, Zhang JY et al (2003) NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421:639–643. doi:10.1038/nature01283

    Article  PubMed  CAS  Google Scholar 

  213. Buytaert E, Dewaele M, Agostinis P (2007) Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochim Biophys Acta 1776:86–107

    PubMed  CAS  Google Scholar 

  214. Dolmans DE, Fukumura D, Jain RK (2003) Photodynamic therapy for cancer. Nat Rev 3:380–387

    CAS  Google Scholar 

  215. Castano AP, Mroz P, Hamblin MR (2006) Photodynamic therapy and anti-tumour immunity. Nat Rev 6:535–545

    CAS  Google Scholar 

  216. Babilas P, Landthaler M, Szeimies RM (2006) Photodynamic therapy in dermatology. Eur J Dermatol 16:340–348

    PubMed  CAS  Google Scholar 

  217. Almeida RD, Manadas BJ, Carvalho AP, Duarte CB (2004) Intracellular signaling mechanisms in photodynamic therapy. Biochim Biophys Acta 1704:59–86

    PubMed  CAS  Google Scholar 

  218. Lyell A (1956) Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 68:355–361. doi:10.1111/j.1365-2133.1956.tb12766.x

    Article  PubMed  CAS  Google Scholar 

  219. Paul C, Wolkenstein P, Adle H et al (1996) Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 134:710–714. doi:10.1111/j.1365-2133.1996.tb06976.x

    Article  PubMed  CAS  Google Scholar 

  220. Nassif A, Bensussan A, Boumsell L et al (2004) Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol 114:1209–1215. doi:10.1016/j.jaci.2004.07.047

    Article  PubMed  CAS  Google Scholar 

  221. Viard I, Wehrli P, Bullani R et al (1998) Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490–493

    Article  PubMed  CAS  Google Scholar 

  222. Diessenbacher P, Hupe M, Sprick MR et al (2008) NF-kappaB inhibition reveals differential mechanisms of TNF versus TRAIL-induced apoptosis upstream or at the level of caspase-8 activation independent of cIAP2. J Invest Dermatol 128:1134–1147. doi:10.1038/sj.jid.5701141

    Article  PubMed  CAS  Google Scholar 

  223. Ito K, Hara H, Okada T, Shimojima H, Suzuki H (2004) Toxic epidermal necrolysis treated with low-dose intravenous immunoglobulin: immunohistochemical study of Fas and Fas-ligand expression. Clin Exp Dermatol 29:679–680. doi:10.1111/j.1365-2230.2004.01635.x

    Article  PubMed  CAS  Google Scholar 

  224. Lamoreux MR, Sternbach MR, Hsu WT (2006) Erythema multiforme. Am Fam Physician 74:1883–1888

    PubMed  Google Scholar 

  225. Wang X, Bregegere F, Frusic-Zlotkin M, Feinmesser M, Michel B, Milner Y (2004) Possible apoptotic mechanism in epidermal cell acantholysis induced by pemphigus vulgaris autoimmunoglobulins. Apoptosis 9:131–143. doi:10.1023/B:APPT.0000018795.05766.1f

    Article  PubMed  CAS  Google Scholar 

  226. Puviani M, Marconi A, Cozzani E, Pincelli C (2003) Fas ligand in pemphigus sera induces keratinocyte apoptosis through the activation of caspase-8. J Invest Dermatol 120:164–167. doi:10.1046/j.1523-1747.2003.12014.x

    Article  PubMed  CAS  Google Scholar 

  227. Trautmann A, Akdis M, Blaser K, Akdis CA (2000) Role of dysregulated apoptosis in atopic dermatitis. Apoptosis 5:425–429. doi:10.1023/A:1009620329213

    Article  PubMed  CAS  Google Scholar 

  228. Trautmann A, Akdis M, Kleemann D et al (2000) T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 106:25–35. doi:10.1172/JCI9199

    Article  PubMed  CAS  Google Scholar 

  229. Farley SM, Dotson AD, Purdy DE et al (2006) Fas ligand elicits a caspase-independent proinflammatory response in human keratinocytes: implications for dermatitis. J Invest Dermatol 126:2438–2451. doi:10.1038/sj.jid.5700477

    Article  PubMed  CAS  Google Scholar 

  230. Farley SM, Purdy DE, Ryabinina OP, Schneider P, Magun BE, Iordanov MS (2008) Fas ligand-induced proinflammatory transcriptional responses in reconstructed human epidermis. Recruitment of the epidermal growth factor receptor and activation of MAP kinases. J Biol Chem 283:919–928. doi:10.1074/jbc.M705852200

    Article  PubMed  CAS  Google Scholar 

  231. Ferrara JL, Levy R, Chao NJ (1999) Pathophysiologic mechanisms of acute graft vs. host disease. Biol Blood Marrow Transplant 5:347–356. doi:10.1016/S1083-8791(99)70011-X

    Article  PubMed  CAS  Google Scholar 

  232. Gilliam AC, Whitaker-Menezes D, Korngold R, Murphy GF (1996) Apoptosis is the predominant form of epithelial target cell injury in acute experimental graft-versus-host disease. J Invest Dermatol 107:377–383. doi:10.1111/1523-1747.ep12363361

    Article  PubMed  CAS  Google Scholar 

  233. Baker MB, Altman NH, Podack ER, Levy RB (1996) The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J Exp Med 183:2645–2656. doi:10.1084/jem.183.6.2645

    Article  PubMed  CAS  Google Scholar 

  234. Braun MY, Lowin B, French L, Acha-Orbea H, Tschopp J (1996) Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease. J Exp Med 183:657–661. doi:10.1084/jem.183.2.657

    Article  PubMed  CAS  Google Scholar 

  235. Hattori K, Hirano T, Miyajima H et al (1998) Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies. Blood 91:4051–4055

    PubMed  CAS  Google Scholar 

  236. Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R (1997) Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 3:1285–1289. doi:10.1038/nm1197-1285

    Article  PubMed  CAS  Google Scholar 

  237. Pohl T, Gugasyan R, Grumont RJ et al (2002) The combined absence of NF-kappa B1 and c-Rel reveals that overlapping roles for these transcription factors in the B cell lineage are restricted to the activation and function of mature cells. Proc Natl Acad Sci USA 99:4514–4519. doi:10.1073/pnas.072071599

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank A. Bredan for editing the manuscript. This research has been supported by Flanders Institute for Biotechnology (VIB) and several grants. European grants: FP6 ApopTrain, MRTN-CT-035624; EC RTD Integrated Project, FP6 Epistem, LSHB-CT-2005-019067; EC RTD Integrated Project, Apo-Sys, FP7-200767. Belgian grants: Interuniversity attraction poles, IAP 6/18. Flemish grants: Fonds Wetenschappelijke Onderzoek Vlaanderen, 3G.0218.06 and G.0133.05; Ghent University grants: BOF-GOA -12.0505.02. S.L. holds a grant of the ‘Fonds voor Wetenschappelijk Onderzoek’. E.H. holds a grant of the ‘Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie’ in Vlaanderen’.

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  1. Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium

    Saskia Lippens, Esther Hoste, Peter Vandenabeele & Wim Declercq

  2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

    Saskia Lippens, Esther Hoste, Peter Vandenabeele & Wim Declercq

  3. Department Molecular and Cell Biology, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium

    Patrizia Agostinis

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  1. Saskia Lippens
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Correspondence to Wim Declercq.

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Lippens, S., Hoste, E., Vandenabeele, P. et al. Cell death in the skin. Apoptosis 14, 549–569 (2009). https://doi.org/10.1007/s10495-009-0324-z

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