Oncogene database

2290

FOXG1

forkhead box G1;FOXG1;forkhead box G1

brain factor 1|brain factor 2|forkhead box protein G1|forkhead-like 1|forkhead-like 2|forkhead-like 3|forkhead-like 4|oncogene QIN

14q13

protein-coding

The winged helix transcription factor Qin is the avian homolog of the mammalian brain factor 1 (BF-1) and has the potential to act as an oncogenic protein. We used representational difference analysis to identify genes that are differentially expressed in chicken embryo fibroblasts (CEF) transformed by Qin. One of the up-regulated Qin targets identified in this analysis is a serine-threonine kinase termed Qik (Qin-induced kinase). Qik belongs to the AMPK/SNF1 kinase family. It is a ubiquitously expressed protein and is upregulated rapidly after a hormone-regulated form of Qin is activated. In vitro kinase tests demonstrate that Qik is capable of autophosphorylation. Elevated levels of Qik transcripts are also observed in Src-transformed cells, suggesting that Src and Qin share some targets.

Using the plasminogen activator inhibitor (PAI) promoter to drive the expression of a reporter gene (mouse CD2), we devised a system to clone negative regulators of the transforming growth factor-beta (TGF-beta) signaling pathway. We infected a TGF-beta-responsive cell line (MvLu1) with a retroviral cDNA library, selecting by fluorescence-activated cell sorter single cells displaying low PAI promoter activity in response to TGF-beta. Using this strategy we cloned the proto-oncogene brain factor-1 (BF-1). BF-1 represses the PAI promoter in part by associating with both unphosphorylated Smad3 (in the cytoplasm) and phosphorylated Smad3 (in the nucleus), thus preventing its binding to DNA. BF-1 also associates with Smad1, -2, and -4; the Smad MH2 domain binds to BF-1, and the C-terminal segment of BF-1 is uniquely and solely required for binding to Smads. Further, BF-1 represses another TGF-beta-induced promoter (p15), it up-regulates a TGF-beta-repressed promoter (Cyclin A), and it reverses the growth arrest caused by TGF-beta. Our results suggest that BF-1 is a general inhibitor of TGF-beta signaling and as such may play a key role during brain development.

Development of basal cell carcinomas (BCCs) in skin is associated with uncontrolled Sonic hedgehog (Shh) signaling, which operates primarily through the Gli family of transcription factors. Gli2 is a mediator of physiological Shh signaling in skin and is sufficient to produce BCCs when overexpressed by use of a Keratin 5 (K5) promoter. Analysis of Gli protein deletion mutants has identified an NH(2)-terminal transcription repressor domain in Gli2 but not Gli1. To assess the potential involvement of the Gli2 repressor domain in skin tumor development, we overexpressed the Gli2DeltaN2 mutant in transgenic mice by use of the K5 promoter. K5-Gli2DeltaN2 mice developed a variety of skin tumors resembling human trichoblastomas, cylindromas, basaloid follicular hamartomas, and rarely, BCCs. In striking contrast, K5-Gli2 mice overexpressing wild-type Gli2 developed only BCCs. Other differences between tumors arising in these two sets of transgenic mice included their gross appearance, growth rate, and predilection for specific body sites. However, the expression levels of Shh target genes, which reflect the magnitude of Shh pathway activation, were not dramatically different. tumors from K5-Gli2DeltaN2 mice, unlike human or mouse BCCs, gave rise to cell lines that constitutively expressed Shh target genes in vitro and were tumorigenic in nude mice. Interestingly, the phenotype of K5-Gli2DeltaN2 mice was strikingly similar to that reported after K5 promoter-driven overexpression of GLI1, which lacks an NH(2)-terminal region homologous to the Gli2 repressor domain. These results underscore the qualitative difference in oncogenicity of GLI1 and Gli2 when overexpressed in skin, and reveal a previously unanticipated role for the Gli2 NH(2) terminus in defining tumor phenotype.

The retroviral oncogene qin, homologue of mammalian brain factor 1 (FOXG1 B), belongs to the family of winged helix transcription factors. Oncogenic transformation by Qin requires sequence-specific DNA binding. Missense mutations in the forkhead domain of Qin modulate its oncogenic transforming ability in chicken embryonic fibroblasts. We used homology model building (threading) techniques to generate atomic structures of wild-type c-Qin and c-Qin mutants, using the solution structure of the forkhead domain of the adipocyte transcription factor as a template (M. J. van Dongen et al., J. Mol. Biol., 296: 351-359, 2000). Energy calculations indicate that the Qin forkhead structure is stabilized primarily by hydrophobic interactions between residues at the helical interface. None of the missense mutations analyzed here were responsible for maintaining the most critical pairwise interactions holding the forkhead domain together. The mutated proteins form the overall structure of the forkhead domain, but the mutations do interfere with DNA binding.

The retroviral oncogene qin codes for a protein that belongs to the winged helix family of transcriptional regulators. The Qin protein is localized in the nucleus and binds to the same DNA consensus sequence as rat brain factor 1 (BF-1). Cellular Qin shows greater affinity to DNA than does viral Qin. Alone or fused to the DNA-binding domain of the yeast GAL4 protein, both Qin proteins act as transcriptional repressors. The major transcriptional repression domain maps to the region of amino acids 252-395 of viral Qin.

We have isolated chicken cDNA clones of the c-qin gene, the cellular counterpart of the v-qin (Chinese for "avian") oncogene of avian sarcoma virus 31. There are several differences between the cellular and the viral qin sequences: (i) two nonconservative amino acid substitutions in the Qin coding region; (ii) a truncation in the carboxyl terminus of the viral protein due to a premature stop codon; (iii) a partial Gag sequence fused to the amino terminus of viral Qin; and (iv) eight cell-coded amino acids which link the cellular Qin coding domain to the viral Gag domain. We have also characterized the expression pattern of c-qin in chicken embryos by in situ hybridization and by Northern blot analysis. c-qin is abundantly expressed in the developing brain, and this expression is restricted to the telencephalon of early embryos.

Avian sarcoma virus 31 contains an oncogene that we have named qin. qin codes for a nuclear protein, Qin, that is a member of the HNF-3/fork head family of transcriptional regulators. Within this family Qin is particularly closely related to rat brain factor 1 (BF-1), a telencephalon-specific gene presumed to play an important role in the development of the mammalian brain.

Chromosomal mapping of the human QIN gene (renamed FKH2 by the Human Genome Organization Nomenclature Committee) was initially accomplished by correlation of the presence of the QIN locus with specific chromosome regions in a rodent-human hybrid panel. This analysis revealed that the human QIN gene maps to chromosome region 14q11.2-->14q32, between the TCR and IGH loci. Further analysis by fluorescence in situ hybridization techniques with a human QIN genomic clone refined the human QIN gene localization to 14q13.