The combination of ubiquitous transcription factors AP‐1 and Sp1 directs keratinocyte‐specific and differentiation‐specific gene expression in vitro

Abstract

Previous studies of epidermal-specific gene promoters suggested that a limited set of transcription factors regulate keratinocyte-specific and differentiation-specific gene expression in the epidermis. In the present study, we investigated the functional importance of AP-1- and Sp1-binding elements in the determination of cell type-specific and differentiation-specific gene expression by transient transfection into undifferentiated and differentiated keratinocytes as well as into various non-epidermal cell lines. Synthesized short AP-1- and/or Sp1-binding elements were inserted into a minimal reporter vector, and the artificial promoter containing both AP-1 and Sp1 elements showed high levels of transcriptional activity only when transfected into differentiated keratinocytes. Promoters containing either the AP-1 or the Sp1 motif alone showed little activity in any of the cells examined. We also found that close proximity of the Sp1 and AP-1 sites is essential for transcriptional activity, suggesting that the physical interaction between Sp1 and AP-1 factors is important for functional activity. These results clearly demonstrate that the combination of ubiquitously expressed transcription factors AP-1 and Sp1 confers keratinocyte specificity and differentiation specificity on the gene expression. Our findings also provide a simple model of the mechanisms underlying regulation of cell type-specific and cell differentiation-specific gene expression by ubiquitously expressed transcription factors.

Transcriptional regulation of peptidylarginine deiminase expression in human keratinocytes

“…Furthermore, Sp3 expression can either activate or repress a promoter activity, depending on the promoter and the type of cell [45][46][47]. Especially in human epidermis, Sp1 and Sp3 are involved in the regulation of genes involved in the keratinocyte differentiation program, including the genes encoding transglutaminase 1 and 3, loricrin, involucrin, keratin K5, Np63, profilaggrin and ATP2C1 [43]. All these results suggest that the ratio of Sp1 and Sp3 bound to the promoter of PADI genes is responsible for the induced expression of PAD1-3 in the upper keratinocyte layers of the epidermis.…”

“…Sp-family of ubiquitous transcription activators, has been shown to regulate the constitutive expression of a considerable number of genes, and to take part in virtually all facets of cellular functions, including proliferation, apoptosis and differentiation [42]. Among the member of this family, Sp1 and Sp3 have been extensively characterized and are known to be co-expressed in several tissues/ cell types and to interact with an identical consensus sequence [42][43][44]. Furthermore, Sp3 expression can either activate or repress a promoter activity, depending on the promoter and the type of cell [45][46][47].…”

Bleomycin Hydrolase Is Regulated Biphasically in a Differentiation- and Cytokine-dependent Manner

“…It is thought to take part in virtually all facets of cellular function, including proliferation, apoptosis, differentiation, and neoplastic transformation (28,29). In human epidermis, Sp-1 is an important regulator of genes participating in epidermal differentiation, including those of involucrin, loricrin, transglutaminase (30), and peptidylarginine deiminase 1, 2, and 3 (27,31,32). MZF-1 is a transcription factor belonging to the Krüpple family of zinc finger proteins and is expressed in totipotent hemopoietic cells, as well as in myeloid progenitors (33,34).…”

Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses

“…Keratinocyte hyperproliferation and aberrant differentiation are hallmarks of psoriasis (Elder et al, 2010, Harden et al, 2015) and skin inflammation is associated with many of the same transcription factors (TFs) required for epidermal differentiation and barrier formation (i.e., AP1, Sp1 and KLF4) (Nakamura et al, 2007, Rossi et al, 1998, Segre et al, 1999, Tsoi et al, 2012, Uluckan et al, 2015). Genes expressed in the later stages of keratinocyte differentiation are frequently also involved in host defense (Table S1).…”