Transcription factor Nrf2 (encoded by Nfe2l2) regulates a battery of detoxifying and antioxidant genes, and Keap1 represses Nrf2 function. When we ablated Keap1, Keap1-deficient mice died postnatally, probably from malnutrition resulting from hyperkeratosis in the esophagus and forestomach. Nrf2 activity affects the expression levels of several squamous epithelial genes. Biochemical data show that, without Keap1, Nrf2 constitutively accumulates in the nucleus to stimulate transcription of cytoprotective genes. Breeding to Nrf2-deficient mice reversed the phenotypic Keap1 deficiencies. These experiments show that Keap1 acts upstream of Nrf2 in the cellular response to oxidative and xenobiotic stress.

To study the effects of retinoic acid on the skin in vivo, we have subverted the activity of endogenous receptors by targeting expression of a dominant negative mutant of retinoic acid receptor ~ (RARe) to the epidermis of transgenic mice. At birth, mice expressing the mutant RAR¢~ transgene exhibited a marked phenotype of a red, shiny skin that was somewhat sticky to touch. Severely affected neonates died within 24 hr. Histological changes in the epidermis were subtle with the phenotypic stratum corneum appearing slightly thinner and more loosely packed than in controls. Electron microscopic studies revealed that lipid multilamellar structures were not present between cells in the stratum corneum of phenotypic mice. When assayed for transepidermal water loss, phenotypic skin lost water at a rate three times faster than controls, suggesting that neonatal lethality resulted from loss of epidermal barrier function. The absence of a functional lipid barrier in transgenic mice first became evident at El7 when lipids were extruded initially into the intercellular space. We have identified a potential pathway linking inhibition of retinoid signaling with disruption of the lipid barrier that involves peroxisome proliferator-activated receptors. This study documents the role of the retinoid signaling pathway in formation and maintenance of a functional epidermis and provides the first evidence that this is mediated in part by modulation of lipid metabolism.

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Melanonychia, which is characterized by brown or black pigmentation within the nail plate, includes heterogeneous conditions such as pigmented nevus, subungual melanoma and lentigo. We treated two cases of subungual melanoma in situ. One case was a 58-year-old woman who suffered from a malignant melanoma in situ of the left third fingernail, who had also suffered from melanonychia of the fingers for more than 30 years. She had a past history of carcinoma of the uterine cervix. The other patient was a 42-year-old man, who suffered from a malignant melanoma in situ of the right fifth fingernail. He had a past history of carcinoma of the stomach for which he had undergone surgery 2 years earlier. Both cases were accompanied by Hutchinson's sign on the fingertip skin, and the presence of this sign led to the correct diagnosis of subungual melanoma in situ. Judging from previously reported cases, it is unlikely that patients with malignant melanoma have an increased risk of carcinoma of the uterine cervix or of the stomach.

We studied the expression of angiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, platelet derived growth factor and hepatocyte growth factor) in cutaneous neurofibroma which arose in on patients with neurofibromatosis-1. Immunohistochemical staining and the reverse transcribed polymerase chain reaction (RT-PCR) method demonstrated vascular endothelial growth factor and basic fibroblast growth factor to be highly expressed in neurofibroma cells at both protein and mRNA level, thus suggesting that vascular endothelial growth factor and basic fibroblast growth factor contribute to both the angiogenesis and hypervascularity of neurofibroma.