{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T02:01:53Z","timestamp":1790042513971,"version":"4.0.1"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,3,4]]},"abstract":"<jats:p>\n                    Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    , resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations (\u201ctwo-hit\u201d cells) was unclear. We compared TSC skin hamartomas (angiofibromas and periungual fibromas) with normal-appearing skin of the same patient, and we observed more proliferation and mTOR activation in hamartoma epidermis. Two-hit cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of\n                    <jats:italic>TSC2<\/jats:italic>\n                    , in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal\u2013epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed with real-time PCR, and increased amounts of epiregulin protein were demonstrated with immunoprecipitation. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6\n                    <jats:italic>in vitro<\/jats:italic>\n                    . These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by two-hit cells in the dermis and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0712397105","type":"journal-article","created":{"date-parts":[[2008,2,21]],"date-time":"2008-02-21T21:09:47Z","timestamp":1203628187000},"page":"3539-3544","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":47,"title":["Mesenchymal\u2013epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas"],"prefix":"10.1073","volume":"105","author":[{"given":"Shaowei","family":"Li","sequence":"first","affiliation":[{"name":"*Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4712;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiko","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"*Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4712;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-an","family":"Wang","sequence":"additional","affiliation":[{"name":"*Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4712;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyuan","family":"Fan","sequence":"additional","affiliation":[{"name":"*Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4712;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshi","family":"Komurasaki","sequence":"additional","affiliation":[{"name":"Molecular Biology Laboratory, Molecular and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 430-1 Yoshino-cho, Saitma-shi, Saitama 331-9530, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Billings","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Pacheco-Rodriguez","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Moss","sequence":"additional","affiliation":[{"name":"Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas N.","family":"Darling","sequence":"additional","affiliation":[{"name":"*Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4712;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,3,4]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yadr.2006.09.004"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi260"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209090"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-4362.1998.00495.x"},{"key":"e_1_3_3_5_2","first-page":"117","article-title":"Pediatric dermatologic surgery: A surgical approach to the cutaneous features of tuberous sclerosis complex.","volume":"20","author":"Sweeney SM","year":"2004","unstructured":"SM Sweeney, Pediatric dermatologic surgery: A surgical approach to the cutaneous features of tuberous sclerosis complex. 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