A Gene for a Novel Zinc-finger Protein Expressed in Differentiated Epithelial Cells and Transiently in Certain Mesenchymal Cells

Abstract

We have identified a novel zinc-finger protein whose mRNA is expressed at high levels in the epidermal layer of the skin and in epithelial cells in the tongue, palate, esophagus, stomach, and colon of newborn mice. Expression in epithelial cells is first detected at the time of their differentiation during embryonic development. In addition, during early embryonic development there is expression in mesenchymal cells of the skeletal primordia and the metanephric kidney which is later downregulated. The expression pattern suggests that the protein could be involved in terminal differentiation of several epithelial cell types and could also be involved in early differentiation of the skeleton and kidney. The carboxyl terminus of the protein contains three zinc fingers with a high degree of homology to erythroid krü ppel-like factor and binds to DNA fragments containing CACCC motifs. The amino-terminal portion of the protein is proline and serine-rich and can function as a transcriptional activator. The chromosomal location of the gene was mapped using mouse interspecific backcrosses and was shown to localize to mouse chromosome 4 and to cosegregate with the thioredoxin gene.During embryogenesis, a single-cell zygote gives rise to a complex organism composed of many cell types which differentiate from their precursors in an intricate process involving the coordinate action of various cytokines, hormones, and growth factors which activate the expression of specific transcription factors in the cell. Many cell-specific transcription factors involved in the differentiation of tissues have been identified: these fall into several broad classes that include helix-loophelix proteins, homeodomain proteins, and zinc-finger proteins. Zinc-finger transcription factors generally contain a cluster of zinc-finger motifs which together bind to specific DNA sequences; they can be divided into several classes based on the sequence and position of the cysteine and histidine residues and other conserved amino acids. The TFIIIA subclass of zincfinger proteins is characterized by an amino acid motif (Cys-X 2-4 -Cys-X 12 -His-X 3-4 -His) that coordinates zinc ions and is involved in DNA binding. Some zinc-finger proteins of the

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

“…in vivo, KLF4 is essential for maintaining terminally differentiated epithelial cells in the lung, skin and gastrointestinal tract (Shields et al, 1996;Segre et al, 1999;Jaubert et al, 2003;Blanchon et al, 2006;Patel et al, 2006). In cultured cells, KLF4 expression is temporally associated with conditions that promote growth arrest, such as serum deprivation, contact inhibition and DNA damage, and constitutive KLF4 expression inhibits DNA synthesis (Garrett-Sinha et al, 1996;Shields et al, 1996;Stone et al, 2002). g-Irradiation increases KLF4 mRNA levels in a p53-dependent manner and similarly correlates with increased expression of p21 (Yoon et al, 2003).…”

Krüppel-like factor 4 exhibits antiapoptotic activity following γ-radiation-induced DNA damage

“…Examples of p53-dependent cell cycle checkpoint target genes following DNA damage include those encoding the cyclindependent kinase inhibitor, p21 WAF1/CIP1 (El-Deiry et al, 1993;Waldman et al, 1995) and 14-3-3d (Hermeking et al, 1997), which lead to arrest at the G 1 /S and G 2 /M boundaries, respectively, in the cell cycle. We previously demonstrated that the gene encoding Kru¨ppel-like factor 4 (KLF4; also called gut-enriched Kru¨ppel-like factor or GKLF) (Garrett-Sinha et al, 1996;Shields et al, 1996) is transcriptionally activated by p53 following DNA damage (Zhang et al, 1998) and causes cell cycle arrest at both the G 1 /S and G 2 /M boundaries (Yoon et al, 2003;Yoon and Yang, 2004). These results indicate that KLF4 is an important factor in mediating the checkpoint functions of p53 following DNA damage.…”

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…KLF4 belongs to a large family of Kruppel-like activators with zinc-finger DNA-binding domains, recognizing the common GC boxes found in many, if not most, promoters (Kaczynski et al, 2003). Unlike other members of the family, expression is confined to specific tissues, such as the gut, skin and thymic epithelia (Garrett-Sinha et al, 1996;Shields et al, 1996;Conkright et al, 1999).…”