The Journal of investigative dermatology
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J. Invest. Dermatol. · Jun 2003
Insulin-like growth factor-I enhances transforming growth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts.
Keloids are benign dermal tumors, characterized by invasive growth of fibroblasts and concomitant increased biosynthesis of extracellular matrix components, with unclear etiology. We previously demonstrated that keloid fibroblasts overexpress insulin-like growth factor-I receptor. In investigating the role of insulin-like growth factor-I receptor overexpression, insulin-like growth factor-I and transforming growth factor-beta interaction was examined in relation to extracellular matrix protein production in cultured human and mouse fibroblasts. ⋯ Insulin-like growth factor-I markedly enhanced transforming growth factor-beta-induced phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor-2. Luciferase assay showed that this synergistic effect was attenuated by the p38 mitogen-activated protein kinase specific inhibitor SB203580 or phosphatidylinositol 3-kinase inhibitor wortmannin, but not by the mitogen-activated protein kinase/extracellular-signal-regulated protein kinase kinase inhibitor PD98059. These results indicate that insulin-like growth factor-I enhances transforming growth factor-beta-induced keloid formation through transforming growth factor-beta postreceptor signal cross-talk, mainly via the p38 mitogen-activated protein kinase/activating transcription factor-2 pathway.
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J. Invest. Dermatol. · Sep 2002
Agonists of peroxisome proliferator-activated receptor gamma inhibit cell growth in malignant melanoma.
Peroxisome proliferator-activated receptor gamma is a member of the nuclear receptor superfamily involved in adipocyte differentiation and glucose homeostasis. There is evidence that peroxisome proliferator-activated receptor gamma may also act as a tumor suppressor. Here, we demonstrate expression of peroxisome proliferator-activated receptor gamma in benign melanocytic naevi, different variants of primary cutaneous melanomas, and melanoma metastases. ⋯ Apoptosis could be induced in melanoma cell lines by incubation with tumor-necrosis-factor-related apoptosis-inducing ligand. In contrast, the growth inhibitory effect of peroxisome proliferator-activated receptor gamma activation was independent of apoptosis and seemed to occur primarily through induction of cell cycle arrest. Our data indicate that melanoma cell growth may be modulated through peroxisome proliferator-activated receptor gamma.
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J. Invest. Dermatol. · Aug 2002
Ultraviolet irradiation alters transforming growth factor beta/smad pathway in human skin in vivo.
Solar ultraviolet irradiation damages human skin and causes premature skin aging and skin cancer. As transforming growth factor beta plays an important role in regulating cell growth and extracellular matrix synthesis, we investigated expression of transforming growth factor beta isoforms, transforming growth factor beta receptors, and transforming growth factor beta regulated Smad transcription factors following irradiation with an ultraviolet B source and solar-simulated ultraviolet irradiation of human skin in vivo. Full-thickness, sun-protected adult human skin expressed transforming growth factor beta1, beta2, and beta3 transcripts in a ratio of 1:5:3, as determined by quantitative real-time reverse transcription polymerase chain reaction. ⋯ Reduced Smad3/4 DNA binding was observed within 4 h following irradiation. Taken together, these results demonstrate that ultraviolet and solar-simulated ultraviolet irradiation alter the transforming growth factor beta/Smad pathway in human skin in vivo. Ultraviolet induction of Smad7 and reduction of transforming growth factor beta2 and transforming growth factor beta type II receptor should diminish transforming growth factor beta signaling, and probably contribute to the decrease of transforming growth factor beta regulated type I and type III procollagen gene expression observed in ultraviolet and solar-simulated ultraviolet irradiated human skin in vivo.
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J. Invest. Dermatol. · Apr 2002
PTEN mutations in eight Spanish families and one Brazilian family with Cowden syndrome.
Cowden syndrome is an autosomal dominant genodermatosis, characterized by the presence of multiple hamartomas in the skin, breast, thyroid, gastrointestinal tract, central nervous system, and an increased risk in developing breast and thyroid carcinomas. Over 80 germline mutations of the tumor suppressor gene PTEN, on chromosome 10q23, have been reported in more than 100 unrelated patients and families; however, questions regarding distribution of the mutations in populations from different geographic areas, and phenotypic expression are still unclear. In this study the results are reported of mutation analysis of PTEN in 13 families from Spain and one family of Brazilian origin with Cowden syndrome. ⋯ In another case, an identical change had been previously reported as a somatic mutation in an endometrial carcinoma. In one family, the patient presented a de novo mutation, which was not detected in his parents. In five patients, the detection of the PTEN germline mutation confirmed their condition, even in the absence of sufficient criteria to make the clinical diagnosis of Cowden syndrome.
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J. Invest. Dermatol. · Feb 2002
Interleukin-1 receptor antagonist allele 2 and familial alopecia areata.
Alopecia areata affects 1%-2% of the population and is hypothesized to be an autoimmune, organ specific T-cell mediated reaction directed against the human hair follicle. It is characterized by loss of hair in patches (alopecia areata) with progression in some individuals to total loss of scalp hair (alopecia totalis) or to loss of all scalp and body hair (alopecia universalis). The interleukin-1 receptor antagonist (IL-1RN) gene was found to be associated with more severe clinical outcome in several chronic inflammatory diseases, including alopecia areata. ⋯ IL-1RN*2 allele was not associated with alopecia totalis and alopecia universalis. A borderline association was observed between IL-1RN and patchy alopecia areata but it was not statistically significant (p =0.06). We also observed an association between IL1-RN*1 allele and patchy alopecia areata (p =0.045).