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Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3 transcription factor as a tumor suppressor in the skin. NRF3 protein expression is strongly downregulated or even absent in invasively growing cancer cells of patients with basal and squamous cell carcinomas (BCC and SCC). NRF3 deficiency promoted malignant conversion of chemically induced skin tumors in immunocompetent mice, clonogenic growth and migration of human SCC cells, their invasiveness in 3D cultures, and xenograft tumor formation. Mechanistically, the tumor-suppressive effect of NRF3 involves HSPA5, a key regulator of the unfolded protein response, which we identified as a potential NRF3 interactor. HSPA5 levels increased in the absence of NRF3, thereby promoting cancer cell survival and migration. Pharmacological inhibition or knock-down of HSPA5 rescued the malignant features of NRF3-deficient SCC cells in vitro and in preclinical mouse models. Together with the strong expression of HSPA5 in NRF3-deficient cancer cells of SCC patients, these results suggest HSPA5 inhibition as a treatment strategy for these malignancies in stratified cancer patients., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Competing Interests: Competing interests: None.

Genodermatoses are rare inherited skin diseases that frequently affect other organs. They often have marked effects on wellbeing and may cause early death. Progress in molecular genetics and translational research has unravelled many underlying pathological mechanisms, and in several disorders with high unmet need, has opened the way for the introduction of innovative treatments. One approach is to intervene where cell-signaling pathways are dysregulated, in the case of overactive pathways by the use of selective inhibitors, or when the activity of an essential factor is decreased by augmenting a molecular component to correct disequilibrium in the pathway. Where inflammatory reactions have been induced by a genetically altered protein, another possible approach is to suppress the inflammation directly. Depending on the nature of the genodermatosis, the implicated protein or even on the particular mutation, to correct the consequences or the genetic defect, may require a highly personalised stratagem. Repurposed drugs, can be used to bring about a "read through" strategy especially where the genetic defect induces premature termination codons. Sometimes the defective protein can be replaced by a normal functioning one. Cell therapies with allogeneic normal keratinocytes or fibroblasts may restore the integrity of diseased skin and allogeneic bone marrow or mesenchymal cells may additionally rescue other affected organs. Genetic engineering is expanding rapidly. The insertion of a normal functioning gene into cells of the recipient is since long explored. More recently, genome editing, allows reframing, insertion or deletion of exons or disruption of aberrantly functioning genes. There are now several examples where these stratagems are being explored in the (pre)clinical phase of therapeutic trial programmes. Another stratagem, designed to reduce the severity of a given disease involves the use of RNAi to attenuate expression of a harmful protein by decreasing abundance of the cognate transcript. Most of these strategies are short-lasting and will thus require intermittent life-long administration. In contrast, insertion of healthy copies of the relevant gene or editing the disease locus in the genome to correct harmful mutations in stem cells is more likely to induce a permanent cure. Here we discuss the potential advantages and drawbacks of applying these technologies in patients with these genetic conditions. Given the severity of many genodermatoses, prevention of transmission to future generations remains an important goal including offering reproductive choices, such as preimplantation genetic testing, which can allow selection of an unaffected embryo for transfer to the uterus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morren, Legius, Giuliano, Hadj-Rabia, Hohl and Bodemer.)

Cutaneous squamous cell carcinomas (SCCs) are frequent heterogeneous tumors arising from sun-exposed regions of the skin and characterized by complex pathogenesis. HOPX is a member of the homeodomain-containing superfamily of proteins holding an atypical homeodomain unable to bind to DNA. First discovered in the heart as a regulator of cardiac development, in the skin, HOPX modulates the terminal differentiation of keratinocytes. There is a particular interest in studying HOPX in squamous skin carcinogenesis because it has the atypical structure and the functional duality as an oncogene and a tumor suppressor gene, reported in different malignancies. In this study, we analyzed the effects of HOPX knockdown and overexpression on SCC tumorigenicity in vitro and in vivo. Our data show that HOPX knockdown in SCC cells inhibits their proliferative and invasive activity through the acceleration of apoptosis. We established that methylation of two alternative HOPX promoters leads to differential expression of HOPX transcripts in normal keratinocytes and SCC cells. Importantly, we report that HOPX acts as an oncogene in the pathogenesis of SCC probably through the activation of the second alternative promoter and the modulation of apoptosis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Impetigo is a contagious bacterial infection that affects the superficial skin layers. Increasing worldwide antimicrobial resistance (AMR) to existing topical agents commonly prescribed to treat impetigo is central to treatment failure. The Worldwide Health Organization developed a global action plan on AMR, but omitted information about AMR stewardship programs for topical antibiotics., Objectives: The review aims to provide information to clinicians and stakeholders regarding AMR and antimicrobial stewardship on topical antimicrobial drugs for impetigo treatment., Methods: The literature searches reviewed the status of AMR to current topical antibiotics in impetigo, current therapeutic behavior, and concordance with antimicrobial stewardship principles. Two international panels convened to discuss the output of the searches, and the results of the panel discussions were used in the development of the manuscript., Results: The literature search included clinical trials, research studies, clinical guidelines, consensus papers, and reviews (if they provided original data), published between January 2008 and May 2019. The articles were selected based on clinical relevancy of impetigo management, clinical efficacy, and safety of the treatment and antimicrobial resistance. The searches resulted in one-hundred and ninety-eight articles. After applying the eligibility criteria, nineteen articles met inclusion criteria and were considered in the present review., Conclusions: While published antimicrobial stewardship guidelines have focused on systemic antibiotics, few studies have attempted to evaluate topical antibiotic prescribing practices for impetigo treatment. Many of the topical impetigo treatments currently in use have developed resistance. The appropriate use of topical ozenoxacin can help eradicate impetigo while minimizing AMR.J Drugs Dermatol. 20(4):366-372. doi:10.36849/JDD.5795.

Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies. Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients' prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Schaller et al.)

Birt-Hogg-Dubé syndrome (BHD) is a rare inherited autosomal dominant disorder caused by germline mutations in the tumour suppressor gene FLCN , encoding the protein folliculin. Its clinical expression typically includes multiple pulmonary cysts, recurrent spontaneous pneumothoraces, cutaneous fibrofolliculomas and renal tumours of various histological types. BHD has no sex predilection and tends to manifest in the third or fourth decade of life. Multiple bilateral pulmonary cysts are found on chest computed tomography in >80% of patients and more than half experience one or more episodes of pneumothorax. A family history of pneumothorax is an important clue, which suggests the diagnosis of BHD. Unlike other cystic lung diseases such as lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis, BHD does not lead to progressive loss of lung function and chronic respiratory insufficiency. Renal tumours affect about 30% of patients during their lifetime, and can be multiple and recurrent. The diagnosis of BHD is based on a combination of genetic, clinical and/or skin histopathological criteria. Management mainly consists of early pleurodesis in the case of pneumothorax, periodic renal imaging for tumour detection, and diagnostic work-up in search of BHD in relatives of the index patient., Competing Interests: Provenance: Commissioned article, peer reviewed. Conflict of interest: C. Daccord reports non-financial support from Boehringer-Ingelheim and Roche, outside the submitted work. Conflict of interest: J-M. Good has nothing to disclose. Conflict of interest: M-A. Morren has nothing to disclose. Conflict of interest: O. Bonny has nothing to disclose. Conflict of interest: D. Hohl has nothing to disclose. Conflict of interest: R. Lazor reports personal fees and non-financial support from Boehringer-Ingelheim, and non-financial support from Roche and Vifor, outside the submitted work., (Copyright ©ERS 2020.)

Netherton syndrome (NS) is a rare skin disorder involving the skin, hair, and immune system. Pathological manifestations are due to unopposed kallikrein peptidase activity because of a SPINK5 gene deficiency. In their article, Gouin et al. explore the role of kallikrein 14 in the stratum granulosum, defining it as an important player implicated in the pathogenesis of NS hair shaft anomalies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer characterized by increased mortality. Here, we show for the first time that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase of the insulin receptor superfamily, plays a pivotal role in the pathogenesis of cSCC. Our data demonstrate that the overexpression of the constitutively active, mutated ALK, ALK F1174L , is sufficient to initiate the development of cSCC and is 100% penetrant. Moreover, we show that cSCC development upon ALK F1174L overexpression is independent of the cell-of-origin. Molecularly, our data demonstrate that ALK F1174L cooperates with oncogenic Kras G12D and loss of p53 , well-established events in the biology of cSCC. This cooperation results in a more aggressive cSCC type associated with a higher grade histological morphology. Finally, we demonstrate that Stat3 is a key downstream effector of ALK F1174L and likely plays a role in ALK F1174L -driven cSCC tumorigenesis. In sum, these findings reveal that ALK can exert its tumorigenic potential via cooperation with multiple pathways crucial in the pathogenesis of cSCC. Finally, we show that human cSCCs contain mutations in the ALK gene. Taken together, our data identify ALK as a new key player in the pathogenesis of cSCC, and this knowledge suggests that oncogenic ALK signaling can be a target for future clinical trials., (© 2020 Gualandi et al.)

Recent progress in molecular engineering, digital imaging and artificial intelligence improve human modern medicine to levels never seen before. Digital pathology becomes the new standard of patient care in dermatology and personalized medicine. It is increasingly used for digital exchange of histological slides, personalized consultations, tumor boards, quantitative image analysis for research purposes and in education. Digital pathology allows automatization and quantification with greater consistency and accuracy than light microscopy. Personalized dermatology is focusing on tailoring therapy to the individual characteristics of each patient and allow to use genetic information in order to develop a treatment plan, uniquely suited to each patient, which in turn leads to improved quality of care and management of each individual., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article. Le laboratoire de DH profite d’un contrat scientifique de la part d’Unilabs.

Competing Interests: Competing interests: The authors have no conflicts of interest to disclose.

The current classification of melanocytic tumors includes clinical, pathological, and molecular data. A subset of lesions remains difficult to classify according to these complex multilayer schemes. We report two cases of deeply infiltrating melanomas with a sclerosing background. The first case occurred on the back of a middle-aged man appearing clinically as a dermatofibroma. The architectural and cytological aspects resembled those of a desmoplastic melanoma but the strong expression of both melanA and HMB45, two stainings usually reported as negative in this entity, raised the question of an alternate diagnosis. The second case was a large, slowly growing, perivulvar tumor in a middle-aged woman. The morphology was complex with a central junctional spitzoid pattern associating an epidermal hyperplasia with large nests of large spindled melanocytes. The dermal component was made of deeply invasive strands and nests of nevoid unpigmented melanocytes surrounded by fibrosis; a perineural invasion was present at the periphery of the lesion. In both cases, aCGH found, among many other anomalies, a chromosomal breakpoint at the BRAF locus. RNA sequencing identified in both an AKAP9-BRAF gene fusion. A complementary resection was performed and no relapses have been observed in the respectively 15 and 6 months of follow-up. Both of these melanomas remained unclassified. We further review the variety of melanocytic tumors associated with such BRAF fusions.

Rare Vascular Diseases (RVD) encompass different types of vessel involvement. Some cause a dilation, others a weakening or tortuosity of the arterial wall, others an obstruction or excessive calcification of arterial walls. Clinical pathway of patients with RVD to diagnosis is often long and complex. Thus, in order to allow early diagnosis and coordinated multidisciplinary management and follow-up, a specialized RVD centre has been set-up at the CHUV, following the framework of the national concept of rare diseases., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêt en relation avec cet article.

Atopic dermatitis (AD) has a well-established association with skin colonization or infection by Staphylococcus aureus, which can exacerbate the disease. However, a causal relationship between specific changes in skin colonization during the first years of life and AD development still remains unclear. In this prospective birth cohort study, we aimed to characterize the association between skin colonization and AD development in 149 white infants with or without a family history of atopy. We assessed infants clinically and collected axillary and antecubital fossa skin swabs for culture-based analysis at birth and at seven time points over the first 2 years of life. We found that at age 3 months, S. aureus was more prevalent on the skin of infants who developed AD later on. S. aureus prevalence was increased on infants' skin at the time of AD onset and also 2 months before it, when compared with age-matched, unaffected infants. Furthermore, at AD onset, infants testing positive for S. aureus were younger than uncolonized subjects. In conclusion, our results suggest that specific changes in early-life skin colonization may actively contribute to clinical AD onset in infancy., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.

Activin has emerged as an important player in different types of cancer, but the underlying mechanisms are largely unknown. We show here that activin overexpression is an early event in murine and human skin tumorigenesis. This is functionally important, since activin promoted skin tumorigenesis in mice induced by the human papillomavirus 8 oncogenes. This was accompanied by depletion of epidermal γδ T cells and accumulation of regulatory T cells. Most importantly, activin increased the number of skin macrophages via attraction of blood monocytes, which was prevented by depletion of CCR2-positive monocytes. Gene expression profiling of macrophages from pre-tumorigenic skin and bioinformatics analysis demonstrated that activin induces a gene expression pattern in skin macrophages that resembles the phenotype of tumor-associated macrophages in different malignancies, thereby promoting angiogenesis, cell migration and proteolysis. The functional relevance of this finding was demonstrated by antibody-mediated depletion of macrophages, which strongly suppressed activin-induced skin tumor formation. These results demonstrate that activin induces skin carcinogenesis via attraction and reprogramming of macrophages and identify novel activin targets involved in tumor formation., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)

Differentiation of proliferative nodules in giant congenital nevi from melanoma arising within such nevi is an important diagnostic challenge. DNA methylation is a well-established epigenetic modification already observed in the earliest stages of carcinogenesis, which increases during melanoma progression. The ten-eleven translocation enzymes catalyze the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), which has recently been reported as an epigenetic hallmark associated with tumor aggressiveness and poor prognosis in a wide variety of cancers. In this study, we analyzed 12 proliferative nodules and 13 melanomas both arising in giant congenital nevi and matched results with a control group including 67 benign and malignant melanocytic lesions. Proliferative nodules displayed high 5-hmC expression levels (90.65%) compared with melanomas with almost complete loss of this marker (7.87%). We showed that low 5-hmC levels in melanomas correlate with downregulation of isocitrate dehydrogenase and ten-eleven translocation families of enzymes implicated in the cytosine methylation cycle. Simultaneously, these enzymes were overexpressed in proliferative nodules leading to strong 5-hmC expression. We emphasize the significance of 5-hmC loss for discrimination of melanomas from benign proliferative nodules arising within giant congenital nevi, and for establishing the correct diagnosis in ambiguous cases when histological and immunohistochemical characteristics are not sufficiently specific., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Melanocytic tumours which colonise basal cell carcinomas (BCC) may be considered as either lentigo maligna (LM) (in situ) or invasive melanomas., Objectives: To highlight the diagnostic approach and long-term prognosis of LM which colonises BCC., Materials and Methods: Using Satter et al.'s classification, we identified a case of BCC colonised by LM and reviewed similar cases in the literature with long-term follow-up., Results: In the absence of melanocytic extension beyond the lamina propria of the BCC compartment, mixed tumours may be considered as LM colonising the BCC, allowing for less invasive surgery. The absence of long-term relapse in our short series supports this diagnosis, rather than invasive melanomas., Conclusion: Our case report, review of the literature, and series follow-up illustrate the most recent assessment of melanocytic/BCC tumours, and guide the physician and the pathologist in their recognition and classification, thus allowing them to make the most appropriate therapeutic decisions.

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)

The homeodomain-only protein homeobox (HOPX) is the smallest known member of the homeodomain-containing protein family, atypically unable to bind DNA. HOPX is widely expressed in diverse tissues, where it is critically involved in the regulation of proliferation and differentiation. In human skin, HOPX controls epidermal formation through the regulation of late differentiation markers, and HOPX expression correlates with the level of differentiation in cutaneous pathologies. In mouse skin, Hopx was additionally identified as a lineage tracing marker of quiescent hair follicle stem cells. This review discusses current knowledge of HOPX structure and function in normal and pathological conditions., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The skin contains many commensal bacteria. For years, these microbes have been considered to be exploiters of the human host for nutrients. However, recent findings indicates that the skin microbiota is also used by the human host to protect himself against invading pathogens as the commensal bacteria have direct antimicrobial capacity and provide factors required to mount a protective immune responses in the skin. While the healthy skin microbiome functions as guardians of host defense, increased or decreased bacterial composition of the skin microbiome (called dysbiosis) leads to skin inflammation and disease. Here we will review the emerging data on the role of distinct types of dysbiosis in the pathogenesis skin diseases and illustrate how the new understanding of the role of the skin microbiome has implications in the clinical management of skin diseases.

Progress in paediatric dermatology is achieved in both research and therapeutic fields. In infectiology, scabies and bed bugs are a scourge for dermatologists, with an important recent outbreak. This article describes the fundamental clinical signs to look for, when suspecting such diagnosis. Hair dermatoscopy seems to be also very precious as a new tool for the diagnosis of ringworm. Regarding eczemas, atopic dermatitis is supported by S. Aureus's skin colonization, the target of eradication of new products in ongoing studies. We will also explain the role of Hemangiol, recently marketed in Switzerland for the treatment of haemangiomas. Alternative beta blockers have also a large number of ongoing projects in the dermatological vascular diseases field. Other various news is to be discovered....

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

We describe a patient with interstitial granuloma annulare associated with subcutaneous injection therapy (SIT) for desensitization to a type I allergy. Asymptomatic, erythematous, violaceous annular patches were located at the injection sites on both her arms. Medical history revealed perennial rhinoconjonctivitis treated with SIT (Phostal Stallergen® cat 100% and D. pteronyssinus/D.farinae 50%:50%).

The history of most cutaneous squamous cell carcinomas (CSCC) is limited to the skin. However, about 4% of these malignancies are at risk of metastasis and can be life-threatening. This risk is determined by clinical and histological elements which are individually recognized, but so far staging systems allow us neither to assess a risk score, nor to adopt a standardized therapeutical approach. This article reviews prognostic factors for CSCC, and underlines the need for the clinician to have all clinical and histological elements available, in order to try to define the best therapeutical strategy for each case, following up-to-date recommendations.

Many significant advances in dermatology were published during 2009, focussing on infectious diseases, inflammatory disorders and oncology. Molecular medicine, as a result of the human genome project, also modifies the field of dermatology. Bioinformatics and biotechnology revolutionize the daily clinical practice in dermatology. A change of paradigm occurs notably in infectious diseases.

Continuous turnover of epithelia is ensured by the extensive self-renewal capacity of tissue-specific stem cells. Similarly, epithelial tumour maintenance relies on cancer stem cells (CSCs), which co-opt stem cell properties. For most tumours, the cellular origin of these CSCs and regulatory pathways essential for sustaining stemness have not been identified. In murine skin, follicular morphogenesis is driven by bulge stem cells that specifically express CD34. Here we identify a population of cells in early epidermal tumours characterized by phenotypic and functional similarities to normal bulge skin stem cells. This population contains CSCs, which are the only cells with tumour initiation properties. Transplants derived from these CSCs preserve the hierarchical organization of the primary tumour. We describe beta-catenin signalling as being essential in sustaining the CSC phenotype. Ablation of the beta-catenin gene results in the loss of CSCs and complete tumour regression. In addition, we provide evidence for the involvement of increased beta-catenin signalling in malignant human squamous cell carcinomas. Because Wnt/beta-catenin signalling is not essential for normal epidermal homeostasis, such a mechanistic difference may thus be targeted to eliminate CSCs and consequently eradicate squamous cell carcinomas.

Netherton syndrome (NS) is a human autosomal recessive skin disease caused by mutations in the SPINK5 gene, which encodes the putative proteinase inhibitor LEKTI. We have generated a transgenic mouse line with an insertional mutation that inactivated the mouse SPINK5 ortholog. Mutant mice exhibit fragile stratum corneum and perinatal death due to dehydration. Our analysis suggests that the phenotype is a consequence of desmosomal fragility associated with premature proteolysis of corneodesmosin, an extracellular desmosomal component. Our mouse mutant provides a model system for molecular studies of desmosomal stability and keratinocyte adhesion, and for designing therapeutic strategies to treat NS., (Copyright 2004 Cold Spring Harbor Laboratory Press)

Cylindromas are benign adnexal skin tumors caused by germline mutations in the CYLD gene. In most cases the second wild-type allele is lost in tumor tissue, suggesting that CYLD functions as tumor suppressor. CYLD is a protein of 956 amino acids harboring a functional deubiquitinating domain at the COOH-terminal end. To shed more light on the function of CYLD, we have performed a yeast two hybrid screen using an HaCaT cDNA library that identified the RING finger protein TRIP (TRAF-interacting protein) as interactor with full-length CYLD. Mapping of the interacting domains revealed that the central domain of CYLD binds to the COOH-terminal end of TRIP. Far Western analysis and coimmunoprecipitations in mammalian cells confirmed that full-length CYLD binds to the COOH-terminal domain of TRIP. Because TRIP is an inhibitor of nuclear factor (NF)-kappaB activation by tumor necrosis factor (TNF), the effect of CYLD on NF-kappaB activation was investigated in HeLa cells. The results established that CYLD down-regulates NF-kappaB activation by TNF-alpha. The inhibition by CYLD depends on the presence of the central domain interacting with TRIP and its deubiquitinating activity. These findings indicate that cylindromas arise through constitutive NF-kappaB activation leading to hyperproliferation and tumor growth.