TWEAK Affects Keratinocyte G2/M Growth Arrest and Induces Apoptosis through the Translocation of the AIF Protein to the Nucleus (original) (raw)
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Journal of Cutaneous Pathology, 2011
Expression of TWEAK in normal human skin, dermatitis and epidermal neoplasms: association with proliferation and differentiation of keratinocytes Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of various inflammatory pathologies and cancer. We aimed to investigate its expression in normal human skin, inflammatory skin diseases and epidermal neoplasms. Methods: Immunohistochemistry for TWEAK was performed in samples of healthy skin, plaque psoriasis, lichen planus, prurigo nodularis, discoid lupus erythematosus, lichen sclerosus, seborrheic keratosis, common warts, actinic keratosis, Bowen's disease, keratoacanthoma and basal and squamous cell carcinoma. Double immunofluorescence was used to investigate co-localization of TWEAK with cytokeratin-10 and proliferating cell nuclear antigen (PCNA). Results: TWEAK was robustly expressed in the epidermis of healthy skin and decreased in inflammatory conditions, both in the context of epidermal hyperplasia and atrophy. Decreased TWEAK immunoreactivity was regularly observed in common warts, actinic keratosis and Bowen's disease, particularly in areas of marked proliferation as evidenced by PCNA-positive nuclei. In squamous cell carcinoma, expression of TWEAK ranged from strong to completely absent, and it mostly corresponded with the expression of cytokeratin-10. TWEAK was absent in keratoacanthoma and basal cell carcinoma. Conclusions: TWEAK is a constitutively expressed epidermal protein whose downregulation might be an early indicator of disturbed differentiation or pathologic proliferation of keratinocytes that accompany inflammatory and neoplastic skin diseases.
Journal of Biological Chemistry, 1999
We have examined the role that individual TGF- isoforms, and in particular TGF-3, play in control of epidermal homeostasis. Mice with a knockout mutation of the TGF-3 gene die a few hours after birth. A fullthickness skin grafting approach was used to investigate the postnatal development and homeostatic control of the skin of these mice. Grafted skin of mice with a disruption of the TGF-3 gene developed similarly to grafts of wild type and TGF-1 knockout animals. However, a strikingly different response was observed after acute treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). When exposed to TPA, the grafted skin of wild type and TGF-1 knockout mice underwent a hyperplastic response similar to that of normal mouse skin. In marked contrast, TPA treatment of TGF-3 knockout grafts induced widespread areas of keratinocyte cell death. Analysis of cultured keratinocytes treated with purified TGF- isoforms revealed that TGF-3 plays a direct and specific function in protecting keratinocytes against TPA-induced cell death. The protective function of TGF-3 on TPA-induced cell death was not because of general suppression of the signaling pathways triggered by this agent, as ERK1/2 activation occurred to a similar if not greater extent in TGF-3-treated versus control keratinocytes. Instead, TGF-3 treatment led to a significant reduction in TPAinduced c-Jun N-terminal kinase activity, which was associated and possibly explained by specific counteracting effects of TGF-3 on TPA-induced disruption of keratinocyte focal adhesions.
Journal of Biological Chemistry, 1999
We have examined the role that individual TGF- isoforms, and in particular TGF-3, play in control of epidermal homeostasis. Mice with a knockout mutation of the TGF-3 gene die a few hours after birth. A fullthickness skin grafting approach was used to investigate the postnatal development and homeostatic control of the skin of these mice. Grafted skin of mice with a disruption of the TGF-3 gene developed similarly to grafts of wild type and TGF-1 knockout animals. However, a strikingly different response was observed after acute treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). When exposed to TPA, the grafted skin of wild type and TGF-1 knockout mice underwent a hyperplastic response similar to that of normal mouse skin. In marked contrast, TPA treatment of TGF-3 knockout grafts induced widespread areas of keratinocyte cell death. Analysis of cultured keratinocytes treated with purified TGF- isoforms revealed that TGF-3 plays a direct and specific function in protecting keratinocytes against TPA-induced cell death. The protective function of TGF-3 on TPA-induced cell death was not because of general suppression of the signaling pathways triggered by this agent, as ERK1/2 activation occurred to a similar if not greater extent in TGF-3-treated versus control keratinocytes. Instead, TGF-3 treatment led to a significant reduction in TPAinduced c-Jun N-terminal kinase activity, which was associated and possibly explained by specific counteracting effects of TGF-3 on TPA-induced disruption of keratinocyte focal adhesions.
Development, 2007
The TAF4 subunit of transcription factor TFIID was inactivated in the basal keratinocytes of foetal and adult mouse epidermis. Loss of TAF4 in the foetal epidermis results in reduced expression of the genes required for skin barrier function, leading to early neonatal death. By contrast, TAF4 inactivation in adult epidermis leads to extensive fur loss and an aberrant hair cycle characterised by a defective anagen phase. Although the mutant epidermis contains few normal anagen-phase hair follicles, many genes expressed at this stage are strongly upregulated indicating desynchronised and inappropriate gene expression. The TAF4 mutant adult epidermis also displays interfollicular hyperplasia associated with a potent upregulation of several members of the EGF family of mitogens. Moreover, loss of TAF4 leads to malignant transformation of chemically induced papillomas and the appearance of invasive melanocytic tumours. Together, our results show that TAF4 is an important regulator of keratinocyte proliferation and has cell-autonomous and non-cell-autonomous tumour suppressor activity.
Journal of Biological Chemistry, 2004
Identification of tumor necrosis factor-␣ (TNF␣) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF␣-targeting therapies, which, although avoiding many of the sideeffects of previous drugs, nonetheless causes other sideeffects, including secondary infections and cancer. By controlling gene expression, TNF␣ orchestrates the cutaneous responses to environmental damage and inflammation. To define TNF␣ action in epidermis, we compared the transcriptional profiles of normal human keratinocytes untreated and treated with TNF␣ for 1, 4, 24, and 48 h by using oligonucleotide microarrays. We found that TNF␣ regulates not only immune and inflammatory responses but also tissue remodeling, cell motility, cell cycle, and apoptosis. Specifically, TNF␣ regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF␣ targets, that attract neutrophils, macrophages, and skinspecific memory T-cells. This implicates TNF␣ in the pathogenesis of psoriasis, fixed drug eruption, atopic and allergic contact dermatitis. TNF␣ promotes tissue repair by inducing basement membrane components and collagen-degrading proteases. Unexpectedly, TNF␣ induces actin cytoskeleton regulators and integrins, enhancing keratinocyte motility and attachment, effects not previously associated with TNF␣. Also unanticipated was the influence of TNF␣ upon keratinocyte cell fate by regulating cell-cycle and apoptosis-associated genes. Therefore, TNF␣ initiates not only the initiation of inflammation and responses to injury, but also the subsequent epidermal repair. The results provide new insights into the harmful and beneficial TNF␣ effects and define the mechanisms and genes that achieve these outcomes, both of which are important for TNF␣-targeted therapies.
Role of TWEAK and Fn14 in tumor biology
Frontiers in Bioscience, 2007
Introduction 2.1. TWEAK and Fn14 structure 2.2. The TWEAK-Fn14 signaling pathway 2.3. TWEAK biological activity in vitro and in vivo 2.4. Phenotypic analysis of TWEAK-null and Fn14-null mice 3. TWEAK as a Regulatory Cytokine in Cancer 3.1. TWEAK gene expression in the tumor microenvironment 3.2. TWEAK effects on tumor cell lines cultured in vitro 3.3. TWEAK as a potential regulator of tumor cell growth in vivo 3.4. TWEAK and tumor inflammation 3.5. TWEAK and tumor angiogenesis 4. Fn14 as a Tumor-specific Cell Surface Marker 4.1. Esophageal cancer 4.2. Liver cancer 4.3. Breast cancer 4.4. Brain cancer 4.5. Mechanistic basis for Fn14 gene activation in tumors? 5. Fn14 as a Tumor Cell Regulatory Molecule 6. Summary 7. Acknowledgments 8. References
Inflammation-mediated skin tumorigenesis induced by epidermal c-Fos
Genes & Development, 2013
Skin squamous cell carcinomas (SCCs) are the second most prevalent skin cancers. Chronic skin inflammation has been associated with the development of SCCs, but the contribution of skin inflammation to SCC development remains largely unknown. In this study, we demonstrate that inducible expression of c-fos in the epidermis of adult mice is sufficient to promote inflammation-mediated epidermal hyperplasia, leading to the development of preneoplastic lesions. Interestingly, c-Fos transcriptionally controls mmp10 and s100a7a15 expression in keratinocytes, subsequently leading to CD4 T-cell recruitment to the skin, thereby promoting epidermal hyperplasia that is likely induced by CD4 T-cell-derived IL-22. Combining inducible c-fos expression in the epidermis with a single dose of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) leads to the development of highly invasive SCCs, which are prevented by using the anti-inflammatory drug sulindac. Moreover, human SCCs display a correlation between c-FOS expression and elevated levels of MMP10 and S100A15 proteins as well as CD4 T-cell infiltration. Our studies demonstrate a bidirectional cross-talk between premalignant keratinocytes and infiltrating CD4 T cells in SCC development. Therefore, targeting inflammation along with the newly identified targets, such as MMP10 and S100A15, represents promising therapeutic strategies to treat SCCs.
2020
To investigate how the CARD14 E138A psoriasis-associated mutation induces skin inflammation, a knock-in mouse strain was generated that allows tamoxifen-induced expression of the homologous Card14 E138A mutation from the endogenous mouse Card14 locus. Heterozygous expression of CARD14 E138A rapidly induced skin acanthosis, immune cell infiltration and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression of CARD14 E138A induced more extensive skin inflammation and a severe systemic disease involving infiltration of myeloid cells in multiple organs, temperature reduction, weight loss and organ failure. This severe phenotype resembled acute exacerbations of generalised pustular psoriasis (GPP), a rare form of psoriasis that can be caused by CARD14 mutations in patients. CARD14 E138A-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14 E138A signalling only in keratinocytes. These results suggest that anti-inflammatory therapies specifically targeting keratinocytes, rather than systemic biologicals, might be effective for GPP treatment early in disease progression.
Serum TWEAK in acne vulgaris: An unknown soldier
Journal of Cosmetic Dermatology, 2019
Acne vulgaris is a common skin problem of the pilosebaceous unit affecting usually adolescents and young adults producing inflammatory and noninflammatory lesions which may heal leaving postacne scars. 1 It has been characterized by excessive sebum production, follicular epithelial hyperkeratosis, and rupture of follicular epithelium, resulting in an increased release of inflammatory-mediating agents. 2 Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) belongs to the TNF superfamily. It has an important role in the regulation of cell growth, apoptosis, angiogenesis, and immune reactions. TWEAK exerts its role via binding to its main receptor, Fn14. 3 It was found to be involved in the pathogenic events of many chronic inflammatory conditions, 4 and targeting this molecule may be a promising therapeutic option for those patients. 5 Despite the chronic inflammatory nature of acne vulgaris, the role of TWEAK in this condition has not been assessed. The current study was carried out to evaluate the serum levels of TWEAK in acne vulgaris patients.