The expression of a novel, epithelium-specific ets transcription factor is restricted to the most differentiated layers in the epidermis

Abstract

Ets proteins have been implicated in the regulation of gene expression during a variety of biological processes, including growth control, differentiation, development and transformation. More than 35 related proteins containing the 'ets domain' have now been found which specifically interact with DNA sequences encompassing the core tetranucleotide GGAA. Although ets responsive genes have been identified in the epidermis, little is known about their distribution and function in this tissue. We have now demonstrated that epidermis and cultured epidermal keratinocytes synthesize numerous ets proteins. The expression of some of these proteins is regulated as a function of differentiation. Among these is a novel ets transcription factor with a dual DNA-binding specificity, which we have called jen. The expression of jen is not only epithelial specific, but it is the only ets protein so far described, and one of the very few transcription factors whose expression is restricted to the most differentiated epidermal layers. We show that two epidermal marker genes whose expression coincides with that of jen are transregulated by this protein in a complex mode which involves interactions with other transcriptional regulators such as Sp1 and AP1.

Dual function of the epithelial specific ets transcription factor, ELF3, in modulating differentiation

“…This repression was not mediated by DNA binding of ELF3. In contrast, ELF3 binds and transactivates the SPRR2A and Endo A (keratin 8) enhancers (Oettgen et al, 1997a) and it also transactivates the TGM3 promoter in cell lines of keratinocyte origin (Andreoli et al, 1997). Furthermore, ELF3 is a potent transactivator of the TGF-b II receptor that is mediated through binding to a 5'-GGAAACAGGAA-3' motif in reverse orientation at +13 to +24 in the TGF-b II receptor gene (Choi et al, 1998).…”

“…This is further re¯ected by the fact that ELF3 (22 kDa) itself is expressed in the terminally di erentiated layer of the epidermis (Andreoli et al, 1997). The latter is consistent with observations that report induction of ELF3 when NEHK cells are switched to media with higher concentration of calcium and the addition of TPA, both of which favor keratinocyte di erentiation and expression of late di erentiation markers such as TGM3 and pro®llagrin (Andreoli et al, 1997). In addition, ELF3 cooperates with Sp1 and AP1 to transactivate the TGM3 and pro®llagrin promoters (Andreoli et al, 1997).…”

“…Additionally, four other groups discovered the same gene. Jen was the term designated to this novel member that resulted from screening a human foreskin keratinocyte cDNA library with a conserved 3' region of the ets domain (Andreoli et al, 1997). A search of expressed sequence tags with an 8 amino acid motif of the carboxyl terminal region of the ets domain led to the identi®cation of the same factor, termed ESX for epithelial restricted with serine box (Chang et al, 1997).…”

“…ELF3 transactivates the transglutaminase 3 (TGM3) promoter in HeLa, HaCaT and normal epidermal cells, but not in ®broblasts and neuroblastoma cells (Andreoli et al, 1997). Of signi®cance, ELF3 binds and transactivates enhancer elements within the SPRR2A and pro®llagrin promoters, which along with the TGM3 promoter, are associated with terminal di erentiation in strati®ed squamous epithelia (Andreoli et al, 1997;Choi et al, 1998;Oettgen et al, 1997a).…”

Exon 4-encoded acidic domain in the epithelium-restricted Ets factor, ESX, confers potent transactivating capacity and binds to TATA-binding protein (TBP)

“…Four other groups have since published on the potential biological and developmental importance of this epithelium-speci®c Ets factor (variably named ESE-1, ELF-3, Jen, or ERT) in non-mammary epithelial systems (Andreoli et al, 1997;Choi et al, 1998;Oettgen et al, 1997a;Tymms et al, 1997). Additionally, a recent study of mouse mammary epithelium resected at various stages of normal gland development showed that ESX expression increases during pregnancy in association with ductal development, declines dramatically during terminal differentiation only to maximally reappear during glandular involution (Neve et al, 1998).…”