Unusual Patterns of Keratin Expression in the Overlying Epidermis of Patients with Dermatofibromas: Biochemical Alterations in the Epidermis as a Consequence of Dermal Tumors

Stoler, Andrea; Duvic, Madeleine; Fuchs, Elaine

doi:10.1111/1523-1747.ep12284397

Cited by 33 publications

(20 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Human psoriasis is characterized by similar hyperkeratosis and parakeratosis 44 and by altered epidermal hyperproliferation, as reflected by thickening of the epidermis and aberrant expression of hyperproliferation-associated keratins K6 and K16 throughout the epidermis, which are normally restricted to sporadic basal keratinocytes and hair follicles. 45 Another similarity we found between the psoriasiform lesions of K14-VEGF mice and human psoriasis was the strong expression of K6 throughout the hyperplastic epidermis of K14-VEGF mice ( Figure 5C); normal mouse skin, with the exception of hair follicles and occasional basal keratinocytes, did not express K6 ( Figure 5B). …”

Section: Abnormal Epidermal Proliferation and Differentiation In K14-mentioning

confidence: 52%

Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis

Xia

Hylton

et al. 2003

Blood

329

305

View full text Add to dashboard Cite

Gene therapy approaches involving vascular endothelial growth factor (VEGF) to promote therapeutic angiogenesis are under consideration for conditions ranging from ischemic heart disease to nonhealing skin ulcers. Here we make the surprising observation that the transgenic delivery of VEGF to the skin results in a profound inflammatory skin condition with many of the cellular and molecular features of psoriasis, including the characteristic vascular changes, epidermal al-

show abstract

Section: Abnormal Epidermal Proliferation and Differentiation In K14-mentioning

confidence: 52%

Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis

Xia

Hylton

et al. 2003

Blood

329

305

View full text Add to dashboard Cite

show abstract

“…5F). Of interest, up-regulated K6 expression is associated with skin diseases such as psoriasis and skin cancer (Stoler et al 1989), suggesting that increased K6 expression in TRF1 D/D K5-Cre epidermis could be related to the appearance of preneoplastic lesions in all mice studied. Finally, these severe skin defects in TRF1 D/D K5-Cre mice were accompanied by a defective epithelial barrier function (Fig.…”

Section: Trf1 Deficiency Leads To Severe Skin Atrophy and Skin Hyperpmentioning

confidence: 99%

Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice

Martínez¹,

Thanasoula²,

Muñoz³

et al. 2009

Genes Dev.

335

518

View full text Add to dashboard Cite

The telomere repeat-binding factor 1 (TERF1, referred to hereafter as TRF1) is a component of mammalian telomeres whose role in telomere biology and disease has remained elusive. Here, we report on cells and mice conditionally deleted for TRF1. TRF1-deleted mouse embryonic fibroblasts (MEFs) show rapid induction of senescence, which is concomitant with abundant telomeric g-H2AX foci and activation of the ATM/ATR downstream checkpoint kinases CHK1 and CHK2. DNA damage foci are rescued by both ATM and ATM/ATR inhibitors, further indicating that both signaling pathways are activated upon TRF1 deletion. Abrogation of the p53 and RB pathways bypasses senescence but leads to chromosomal instability including sister chromatid fusions, chromosome concatenation, and occurrence of multitelomeric signals (MTS). MTS are also elevated in ATR-deficient MEFs or upon treatment with aphidicolin, two conditions known to induce breakage at fragile sites, suggesting that TRF1-depleted telomeres are prone to breakage. To address the impact of these molecular defects in the organism, we deleted TRF1 in stratified epithelia of TRF1 D/D K5-Cre mice. These mice die perinatally and show skin hyperpigmentation and epithelial dysplasia, which are associated with induction of telomere-instigated DNA damage, activation of the p53/p21 and p16 pathways, and cell cycle arrest in vivo. p53 deficiency rescues mouse survival but leads to development of squamous cell carcinomas, demonstrating that TRF1 suppresses tumorigenesis. Together, these results demonstrate that dysfunction of a telomere-binding protein is sufficient to produce severe telomeric damage in the absence of telomere shortening, resulting in premature tissue degeneration and development of neoplastic lesions.[Keywords: Telomeres; TRF1; DNA damage; chromosomal instability; conditional knockout mice; cancer] Supplemental material is available at http://www.genesdev.org.

show abstract

“…Thus, although the biochemical program of terminal differentiation was characteristic of a number of hyperproliferative skin diseases, the changes in K14/K5 and K6/K16 expression did not seem to perturb the overall morphology of terminal differentiation. Indeed, cumulative studies over the past several years have indicated that the altered patterns I of keratin expression often associated with hyperproliferative diseases can be attributed to ehvironmental changes rather than hyperproliferation or abnormalifies in the program of terminal differentiation per se (Mansbridge and Hanawalt 1988;Kopan and Fuchs 1989;Schermer et al 1989;Stoler et al 1989;Choi and Fuchs 1990), In addition to retinoids 1988;Choi and Fuchs 1989), TGF-~ may now be included in this list of environmental factors.…”

Section: Tgf-~ the Balance Between Growth And Differentiation And Pmentioning

confidence: 99%

Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation.

Vassar¹,

Fuchs²

1991

Genes Dev.

387

299

View full text Add to dashboard Cite

Transforming growth factor-,, (TGF-,q is thought to be the major autocrine factor controlling growth in epidermal cells. To explore further the role of TGF-~ in epidermal growth and differentiation, we used a human keratin K14 promoter to target expression of rat TGF-~ cDNA to the stratified squamous epithelia of transgenic mice. Unexpectedly, the only regions of epidermis especially responsive to TGF-~ overexpression were those that were normally thick and where hair follicle density was typically low. This included most, if not all, body skin from 2-day-to 2-week-old mice, and ear, footpad, tail, and scrotum skin in adult mice. In these regions, excess TGF-~ resulted in thicker epidermis and more stunted hair growth. Epidermal thickening was attributed both to cell hypertrophy and to a proportional increase in the number of basal, spinous, granular, and stratum corneum cells. During both postnatal development and epidermal differentiation, responsiveness to elevated TGF-c~ seemed to correlate with existing epidermal growth factor (EGF) receptor levels, and we saw no evidence for TGF-~-mediated control of EGF receptor (EGFR) expression. In adults, no squamous cell carcinomas were detected, but benign papillomas were common, developing primarily in regions of mechanical irritation or wounding. In addition, adult transgenic skin that was still both sensitive to TGF-, and subject to mild irritation displayed localized regions of leukocytic infiltration and granular layer loss, characteristics frequently seen in psoriasis in humans. These unusual regional and developmental effects of TGF-c~ suggest a natural role for the growth factor in (1) controlling epidermal thickness during development and differentiation, (2) involvement in papilloma formation, presumably in conjunction with TGF-I3, and (3) involvement in psoriasis, in conjunction with some as yet unidentified secondary stimulus stemming from mild mechanical irritation/bacterial infection.

show abstract

Unusual Patterns of Keratin Expression in the Overlying Epidermis of Patients with Dermatofibromas: Biochemical Alterations in the Epidermis as a Consequence of Dermal Tumors

Cited by 33 publications

References 46 publications

Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis

Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis

Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice

Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation.

Contact Info

Product

Resources

About