ZAS: C2H2 zinc finger proteins involved in growth and development

Abstract

A ZAS gene encodes a large protein with two separate C2H2 zinc finger pairs that independently bind to specific DNA sequences, including the kappaB motif. Three paralogous mammalian genes, ZAS1, ZAS2, and ZAS3, and a related Drosophila gene, Schnurri, have been cloned and characterized. The ZAS genes encode transcriptional proteins that activate or repress the transcription of a variety of genes involved in growth, development, and metastasis. In addition, ZAS3 associates with a TNF receptor-associated factor to inhibit NF-kappaB- and JNK/ SAPK-mediated signaling of TNF-alpha. Genetic experiments show that ZAS3 deficiency leads to proliferation of cells and tumor formation in mice. The data suggest that ZAS3 is important in controlling cell growth, apoptosis, and inflammation. The potent vasoactive hormone endothelin and transcription factor AP2 gene families also each consist of three members. The ZAS, endothelin, and transcription factor AP2 genes form several linkage groups. Knowledge of the chromosomal locations of these genes provides valuable clues to the evolution of the vertebrate genome.

Figure 1

The protein structure of the ZAS gene family. (A) Protein domains and motifs. Red boxes, C₂H₂ zinc fingers; green boxes, serine-rich regions; purple boxes, conserved middle region; light blue boxes, conserved linker region; dark blue boxes, leucine zippers; square lollipop, GTPase motif; and yellow lollipops, tyrosine phosphorylation sites. (B) Conservation of the zinc finger pairs. Completely conserved residues are shown in green, identical residues are shown in yellow, similar residues are shown in cyan, and different residues are shown in white. In the consensus sequence, identical residues are shown in upper cases, similar residues are shown in lower cases, and gaps are nonconserved residues.

Figure 2

Phylogenetic analyses of the ZAS protein family. (A) Distance matrix scores between ZAS proteins. h, human; m, mouse; and r, rat. (B) Phylogenetic tree of seven full-length ZAS proteins and Shn. (C) Phylogenetic tree of human and mouse ZAS proteins and Shn.

Figure 3

Conservation of the protein-coding regions of the ZAS genes. The sequence of the longest cDNA of each ZAS gene was retrieve from the GenBank databases and compared with the hZAS3 cDNA using the computer program PipMaker (60). The corresponding hZAS3 protein is shown at the top as a reference and a graphical output of the sequence alignments is shown below. The x-axis shows the nucleotide numbering of the hZAS3 cDNA sequence. Protein-coding region is shown in thicker box and untranslated regions are shown in thinner boxes. ZF, zinc finger; P/NLS/S, prolines/nuclear localization signal/serines; AS, acidic residues and serine-rich region; and LZ, leucine zipper.

Figure 4

The exon–intron organization of the mammalian ZAS and Shn genes. Thicker boxes or lines represent protein-coding sequences and thinner boxes or lines represent untranslated sequences. Exons that have been shown to be involved in alternative splicing are shown in red. The additional transcription termination exon, exon 5b, of hZAS3 is shown in green. The regions in Shn encoding for zinc fingers are shown in yellow. EDN, endothelin gene.

Figure 5

The chromosomal locations of the human ZAS, EDN, and TFAP2 genes. (A) Gene loci distributed on three chromosomes. (B) Relative locations of the genes showing different linkage groups. To enhance the visual, ZAS genes are shown in red, TFAP2 genes are shown in yellow, and EDN genes are shown in blue.

Figure 6

A hypothetical evolutionary scheme of the ZAS, EDN, and TFAP2 gene families. Red arrows represent DNA breakages, black circles represent centromeres, and a curved arrow represents a pericentric chromosome inversion.