Cylindromatosis and the CYLD gene: new lessons on the molecular principles of epithelial growth control

Analysing cylindromatosis and the associated defects in the CYLD gene is providing novel insights into the molecular principles of epithelial growth control and carcinogenesis in, and beyond, the skin. In this review, we summarize the histopathology and histogenesis of cylindromas, and the available genetic information on patients with these skin appendage tumors. Focusing on recent data concerning the normal functions and signaling interactions of the CYLD gene product, we explain how CYLD interferes with TNF‐α or TLR‐mediated signaling as well as with JNK or NF‐κB‐dependent p65/50 signaling to limit inflammation. In addition, we delineate how CYLD interferes with activation of the proto‐oncogene Bcl3 and with cyclin D1 expression to limit tumorigenesis, and chart how tumor growth‐promoting agents or UV light and inflammatory mediators can activate CYLD. We argue that these recent insights into CYLD function and cylindroma pathogenesis may lead to the development of novel molecular strategies for cancer prevention and treatment. BioEssays 29:1203–1214, 2007. © 2007 Wiley Periodicals, Inc.

[1]  G. Mosialos,et al.  A Drosophila ortholog of the human cylindromatosis tumor suppressor gene regulates triglyceride content and antibacterial defense , 2007, Development.

[2]  R. Bresalier.  Print and media review , 2007 .

[3]  Liangdan Sun,et al.  Diverse phenotype of Brooke–Spiegler syndrome associated with a nonsense mutation in the CYLD tumor suppressor gene , 2006, Experimental dermatology.

[4]  J. Derry,et al.  Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. , 2006, The Journal of clinical investigation.

[5]  Ji-Yeon Kim,et al.  Up-regulation of Cyclin D1 by HBx Is Mediated by NF-κB2/BCL3 Complex through κB Site of Cyclin D1 Promoter* , 2006, Journal of Biological Chemistry.

[6]  Michael Karin,et al.  Regulation and Function of IKK and IKK-Related Kinases , 2006, Science's STKE.

[7]  A. Fleig,et al.  TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD. , 2006, Cellular signalling.

[8]  R. Szigeti,et al.  CYLD mutations underlie Brooke–Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes , 2006, Clinical genetics.

[9]  F. Giancotti,et al.  Faculty Opinions recommendation of Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. , 2006 .

[10]  G. Cotsarelis.  Epithelial stem cells: a folliculocentric view. , 2006, The Journal of investigative dermatology.

[11]  R. Bernards,et al.  An evaluation of the efficacy of topical application of salicylic acid for the treatment of familial cylindromatosis , 2006, The British journal of dermatology.

[12]  Ramin Massoumi,et al.  Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF-κB Signaling , 2006, Cell.

[13]  R. Paus,et al.  Cylindroma as tumor of hair follicle origin. , 2006, The Journal of investigative dermatology.

[14]  Shao-Cong Sun,et al.  Regulation of T cell development by the deubiquitinating enzyme CYLD , 2006, Nature Immunology.

[15]  Desmond J. Tobin,et al.  NF-κB transmits Eda A1/EdaR signalling to activate Shh and cyclin D1 expression, and controls post-initiation hair placode down growth , 2006, Development.

[16]  Jian-Dong Li,et al.  The Tumor Suppressor Cylindromatosis (CYLD) Acts as a Negative Regulator for Toll-like Receptor 2 Signaling via Negative Cross-talk with TRAF6 and TRAF7* , 2005, Journal of Biological Chemistry.

[17]  G. Cotsarelis.  Gene expression profiling gets to the root of human hair follicle stem cells. , 2005, The Journal of clinical investigation.

[18]  René Bernards,et al.  A Genomic and Functional Inventory of Deubiquitinating Enzymes , 2005, Cell.

[19]  P. Schneiderman,et al.  Genetics of skin appendage neoplasms and related syndromes , 2005, Journal of Medical Genetics.

[20]  M. Caligiuri,et al.  The BRG1- and hBRM-Associated Factor BAF57 Induces Apoptosis by Stimulating Expression of the Cylindromatosis Tumor Suppressor Gene , 2005, Molecular and Cellular Biology.

[21]  Shao-Cong Sun,et al.  Regulation of the Deubiquitinating Enzyme CYLD by IκB Kinase Gamma-Dependent Phosphorylation , 2005, Molecular and Cellular Biology.

[22]  M. Gill,et al.  Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. , 2005, The Journal of investigative dermatology.

[23]  A. Coulson,et al.  Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans , 2005, Nature.

[24]  R. Paus,et al.  Molecular principles of hair follicle induction and morphogenesis , 2005, BioEssays : news and reviews in molecular, cellular and developmental biology.

[25]  G. Stinco,et al.  Carcinosarcoma arising in a patient with multiple cylindromas. , 2005, The American Journal of dermatopathology.

[26]  Shao-Cong Sun,et al.  Negative Regulation of JNK Signaling by the Tumor Suppressor CYLD* , 2004, Journal of Biological Chemistry.

[27]  Y. Matsuo,et al.  The CAP-Gly domain of CYLD associates with the proline-rich sequence in NEMO/IKKgamma. , 2004, Structure.

[28]  Lin-Feng Chen,et al.  NF-κB Is Essential for Induction of CYLD, the Negative Regulator of NF-κB , 2004, Journal of Biological Chemistry.

[29]  K. Grzeschik,et al.  Multiple Familial Trichoepithelioma Caused by Mutations in the Cylindromatosis Tumor Suppressor Gene , 2004, Cancer Research.

[30]  T. Noda,et al.  Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix. , 2004, International journal of oncology.

[31]  Xuejun Zhang,et al.  Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma. , 2004, The Journal of investigative dermatology.

[32]  D. Hohl,et al.  The Tumor Suppressor CYLD Interacts with TRIP and Regulates Negatively Nuclear Factor κB Activation by Tumor Necrosis Factor , 2003, The Journal of experimental medicine.

[33]  B. Aggarwal.  Signalling pathways of the TNF superfamily: a double-edged sword , 2003, Nature Reviews Immunology.

[34]  René Bernards,et al.  Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB , 2003, Nature.

[35]  A. Ashworth,et al.  CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members , 2003, Nature.

[36]  G. Courtois,et al.  The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination , 2003, Nature.

[37]  Murad Alam,et al.  Herpes Zoster and Postherpetic Neuralgia,2nd revised and enlarged edition (Pain Research and Clinical Management, vol 11) , 2003 .

[38]  H. Winter,et al.  K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath-specific type II epithelial keratins of the human hair follicle. , 2003, The Journal of investigative dermatology.

[39]  Jennifer Y. Zhang,et al.  NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia , 2003, Nature.

[40]  Y. Dong,et al.  Systematic functional analysis of the Caenorhabditis elegans genome using RNAi , 2003, Nature.

[41]  M. Karin,et al.  Missing Pieces in the NF-κB Puzzle , 2002, Cell.

[42]  R. Timpl,et al.  Defective laminin 5 processing in cylindroma cells. , 2002, The American journal of pathology.

[43]  H. Müller-Hermelink,et al.  Spiradenocylindroma of the Kidney: Clinical and Genetic Findings Suggesting a Role of Somatic Mutation of the CYLD1 Gene in the Oncogenesis of an Unusual Renal Neoplasm , 2002, The American journal of surgical pathology.

[44]  W. Birchmeier,et al.  Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. , 2001, Development.

[45]  H. Kurzen,et al.  Malignant transformation of multiple dermal cylindromas , 2001, The British journal of dermatology.

[46]  A. Ashworth,et al.  Identification of the familial cylindromatosis tumour-suppressor gene , 2000, Nature Genetics.

[47]  A. Israël.  The IKK complex: an integrator of all signals that activate NF-κB? , 2000 .

[48]  W. Funkhouser,et al.  Selective activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/p52 and for Bcl-3 , 2000, Oncogene.

[49]  Michael Karin,et al.  The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling , 2000 .

[50]  L. Ährlund‐Richter,et al.  Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. , 1999, Cancer research.

[51]  D. Elder,et al.  The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. , 1998, Journal of cell science.

[52]  A. Peraud,et al.  p53 mutations in sweat gland carcinomas , 1998, International journal of cancer.

[53]  P. Khavari,et al.  Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB , 1998 .

[54]  D. Alberts,et al.  Effect of retinol in preventing squamous cell skin cancer in moderate-risk subjects: a randomized, double-blind, controlled trial. Southwest Skin Cancer Prevention Study Group. , 1997, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[55]  M. Stratton,et al.  The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas. , 1996, Oncogene.

[56]  F. Watt,et al.  Suprabasal integrin expression in the epidermis of transgenic mice results in developmental defects and a phenotype resembling psoriasis , 1995, Cell.

[57]  M. Stratton,et al.  Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12–q13: evidence for its role as a tumour suppressor gene , 1995, Nature Genetics.

[58]  W. Vloten,et al.  Familial cutaneous cylindromas: investigations in five generations of a family. , 1995, Journal of the American Academy of Dermatology.

[59]  R. Hennekam,et al.  Dermal eccrine cylindromatosis. , 1994, Journal of medical genetics.

[60]  W. V. van Vloten,et al.  Cutaneous cylindroma with malignant transformation , 1993, Cancer.

[61]  Fiona M. Watt,et al.  Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression , 1993, Cell.

[62]  R. Cardiff,et al.  v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: effects of phorbol esters and retinoic acid. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[63]  H. Zarem.  Tumors of the epidermal appendages. , 1987, Clinics in plastic surgery.

[64]  R. Wells,et al.  Ancell-Spiegler cylindromas (turban tumours) and Brooke-Fordyce Trichoepitheliomas: evidence for a single genetic entity. , 1968, Journal of medical genetics.

[65]  G. B. Dowling.  Epithelioma Adenoides Cysticum , 1927, Proceedings of the Royal Society of Medicine.

[66]  E. Spiegler.  Ueber Endotheliome der Haut , 1899, Archiv für Dermatologie und Syphilis.

[67]  A. Bosserhoff,et al.  Reduced expression of CYLD in human colon and hepatocellular carcinomas. , 2007, Carcinogenesis.

[68]  Ji-Yeon Kim,et al.  Up-regulation of cyclin D1 by HBx is mediated by NF-kappaB2/BCL3 complex through kappaB site of cyclin D1 promoter. , 2006, The Journal of biological chemistry.

[69]  G. Piérard,et al.  Distinct expression patterns of alpha1 (IV) and alpha5 (IV) collagen chains in cylindroma and malignant cylindroma. , 2005, International journal of molecular medicine.

[70]  G. T. Bowden,et al.  Prevention of non-melanoma skin cancer by targeting ultraviolet-B-light signalling , 2004, Nature Reviews Cancer.

[71]  Lin-Feng Chen,et al.  NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. , 2004, The Journal of biological chemistry.

[72]  K. Brand,et al.  Involvement of NF-κB signalling in skin physiology and disease , 2003 .

[73]  Jennifer Y. Zhang,et al.  NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. , 2003, Nature.

[74]  M. Lindsay.  Target discovery , 2003, Nature Reviews Drug Discovery.

[75]  C. Pickart,et al.  Mechanisms underlying ubiquitination. , 2001, Annual review of biochemistry.

[76]  S. Seal,et al.  Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12–q13 , 2000, Human Genetics.

[77]  M. Karin,et al.  The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. , 2000, Seminars in immunology.

[78]  L. Requena,et al.  Neoplasms With Apocrine Differentiation , 1998 .

[79]  D. Brash,et al.  Skin precancer. , 1998, Cancer surveys.

[80]  P. Khavari,et al.  Alterations in NF-kappaB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kappaB. , 1998, Proceedings of the National Academy of Sciences of the United States of America.