Use of monospecific antisera and cRNA probes to localize the major changes in keratin expression during normal and abnormal epidermal differentiation.

Abstract

We report here the isolation and characterization of three antisera, each of which is specific for a single keratin from one of the three different pairs (K1/K10, K14/K5, K16/K6) that are differentially expressed in normal human epidermis and in epidermal diseases of hyperproliferation. We have used these antisera in conjunction with monospecific cRNA probes for epidermal keratin mRNAs to investigate pathways of differentiation in human epidermis and epidermal diseases in vivo and in epidermal cells cultured from normal skin and from squamous cell carcinomas in vitro. Specifically, our results suggest that: (a) the basal-specific keratin mRNAs are down-regulated upon commitment to terminal differentiation, but their encoded proteins are stable, and can be detected throughout the spinous layers; (b) the hyperproliferation-associated keratin mRNAs are expressed at a low level throughout normal epidermis when their encoded proteins are not expressed, but are synthesized at high levels in the suprabasal layers of hyperproliferating epidermis, coincident with the induced expression of the hyperproliferation-associated keratins in these cells; and (c) concomitantly with the induction of the hyperproliferation-associated keratins in the suprabasal layers of the epidermis is the down- regulation of the expression of the terminal differentiation-specific keratins. These data have important implications for our understanding of normal epidermal differentiation and the deviations from this process in the course of epidermal diseases of hyperproliferation.

Mechanistic Effects of Long-Term Ultraviolet B Irradiation Induce Epidermal and Dermal Changes in Human Skin Xenografts

“…82 In stratified epithelia, it has been suggested that K6 and K16 are up-regulated during chronic hyperproliferation, such as in psoriatic skin, or abnormal differentiation, such as a cancer, and that the ubiquitous expression of K6 and K16 is correlated with changes in keratinocyte differentiation. 77,[83][84][85][86] In agreement with these documents, overexpression of the human K16 gene in transgenic mice has been reported to initiate re-organization of the intermediate filament network in keratinocytes in both outer root sheath and epidermis, resulting in aberrant keratinization and hyperproliferation as well as the rescue of the lethal skin blistering phenotype of K14-null mice. 87,88 These observations indicate that K6 and it partners K16 and/or K17 play a direct role in eliciting the cutaneous morphological changes to regulate epidermal proliferation and differentiation.…”

Abnormalities of epidermal differentiation associated with expression of the human papillomavirus type 1 early region in transgenic mice

“…The histological appearance of the affected mouse tails strongly suggests that the epidermal cells are hyperproliferative, and expression of keratins 6 and 16 as seen in the tails is generally associated with epidermal hyperproliferation (Weiss et al, 1984;Stoler et al, 1988). Concomitantly with the expression of keratins 6 and 16, the differentiation-specific keratins 1 and 10 were downregulated to undetectable levels, as observed in the productively infected cells within HPV-1 warts (Breitburd et al, 1987).…”

“…Expression of keratins K6 and K16 has been linked with epithelial hyperproliferation (Weiss et al, 1984;Stoler et al, 1988), although as shown in Fig. 6(g), K6 is expressed in the outer root sheath of the hair follicles in normal epidermis and low levels of K 16 were detected in the basal layer (not shown).…”

“…Keratin K10 is generally associated with normal differentiation of squamous epithelium (Moll et al, 1982;Stoler et al, 1988), and as expected normal mouse tail showed strong expression of K10 throughout the suprabasal layers (Fig. 6d).…”

Complete Cytolysis and Neonatal Lethality in Keratin 5 Knockout Mice Reveal Its Fundamental Role in Skin Integrity and in Epidermolysis Bullosa Simplex

“…In unaffected animals, they are restricted to hair follicles and foot sole epidermis and are absent in interfollicular epidermis (Takahashi et al, 1998;Rothnagel et al, 1999). After mechanical stress or tissue injury or as a result of hyperproliferation or hypoproliferation (Weiss et al, 1984;Stoler et al, 1988;Sellheyer et al, 1993;Wilson et al, 1994;Porter et al, 1998), particularly K6 is strongly induced in interfollicular epidermis. Therefore, we investigated the relationship between the extent of tissue damage in E18.5 and neonatal K5 Ϫ/Ϫ mice and the induction of K6.…”