Oncogene database

2672

GFI1

growth factor independent 1 transcription repressor;GFI1;growth factor independent 1 transcription repressor

growth factor independence-1|growth factor independent protein 1|zinc finger protein 163|zinc finger protein Gfi-1

1p22

protein-coding

Gfi-1 was first cloned from rats (and subsequently from mice, chickens, and humans) and was found to be a 55-kDa protein that bound to DNA in a sequence-specific manner to act as a transcriptional repressor and proto-oncogene. Using PCR, a Gfi-1 homologous cDNA (mdGfi-1) was cloned from the house fly, Musca domestica. Comparison of the mdGfi-1-deduced amino acid sequence with those of vertebrates indicates only moderate overall homology (40.9-43.0% identity). However, these proteins are highly conserved when the zinc finger domains are compared, with mdGfi-1 having 81.0-82.2% identity to the vertebrate homologues. Within each of the six zinc finger domains there are three amino acids that are predicted to contact the DNA and these amino acids are 100% identical for ALL six domains for ALL species. Given that Gfi-1 is highly conserved from insects to vertebrates suggests this may be an important transcription factor in many taxa.

Gfi-1 is a zinc finger transcriptional repressor originally recognized for its role in T cell differentiation and lymphomas. Recent experiments reveal that gene-targeted Gfi-1-deficient mice are neutropenic and that Gfi-1 mutations cause human neutropenia. In both cases, myeloid progenitor cells lose the ability to distinctly differentiate granulocytes from monocytes. The molecular mechanism of the hematopoietic abnormalities caused by Gfi-1 deficiency remains undetermined because of a lack of known Gfi-1 target genes. To identify Gfi-1 targets in vivo, we performed large-scale chromatin immunoprecipitation analysis on a set of 34 candidate genes in myeloblast (KG-1 and HL-60), monoblast (U937), and T lymphocyte cell lines (Jurkat), in concert with RT-PCR-based expression profiling. We identified 32 Gfi-1 binding sites in a functionally variable set of 16 genes, including complements of cell-cycle regulators, transcription factors, and granulocyte-specific markers. Cluster analysis of expression patterns and chromatin immunoprecipitation data reveals that Gfi-1 targets a subset of genes differentiating hematopoietic lineages and therefore plays a relatively superior role in the hierarchy of factors governing stem cell differentiation.

Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic. We therefore screened GFI1 as a candidate for association with neutropenia in affected individuals without mutations in ELA2 (encoding neutrophil elastase), the most common cause of severe congenital neutropenia (SCN; ref. 3). We found dominant negative zinc finger mutations that disable transcriptional repressor activity. The phenotype also includes immunodeficient lymphocytes and production of a circulating population of myeloid cells that appear immature. We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation.

1,25-Dihydroxyvitamin D (1,25D) inhibits growth of prostate cancer cells and has been proposed to play a protective role in prostate cancer. However, 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1), the enzyme responsible for the cellular synthesis of 1,25D, is repressed in prostate cancer cells. Recently, we have identified a role for the transcription factor, Growth Factor Independent-1 (GFI1) in the repression of the CYP27B1 gene in human prostate cancer cell lines. GFI1 is known to form a large protein complex with co-repressors that recruit histone deacetylases. We have proposed a model for the molecular repression of CYP27B1 gene expression. The formation of such a repressive complex on the inhibitory domain of the CYP27B1 gene in prostate cancer cells could lead to the silencing of gene expression either by inactivating nearby enhancer or proximal promoter domains and lead to cancer progression by reducing local production of 1,25D. These studies demonstrate that GFI1 may play a significant role in the down regulation of endogenous production of 1,25D in prostate cancer cells and could provide a novel insight to future diagnosis and treatment.

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate enhancer hijacking as an efficient mechanism driving oncogene activation in a childhood cancer.

mutations in the Caenorhabditis elegans gene pag-3 result in misexpression of touch receptor-specific genes in the BDU interneurons and in motility defects. We cloned pag-3 and found that the gene encodes a C2H2-type zinc finger protein related to the mammalian GFI-1 protein. Sequencing of the three pag-3 alleles showed that two apparent null alleles encode a nonsense mutation before the zinc fingers and a missense mutation in the fourth zinc finger that changes a coordinating histidine to a tyrosine. The third allele contains a nonsense mutation in the N-terminal region but is not a null allele. Northern analysis showed that a single pag-3 transcript of about 1.6 kb is present in embryos and L1, L2 and L3 larvae. pag-3 message levels were about twofold higher in pag-3 mutants than in wild-type animals, which suggested that pag-3 may negatively regulate its own expression. pag-3lacZ fusion genes were expressed in the BDU interneurons, the touch neurons, 11 VA and 11 VB ventral cord motor neurons, two AVF interneurons and in unidentified neurons of the retrovesicular ganglion. The BDU neurons and the ALM touch neurons are lineal sister cells in the AB.a lineage and the VA and VB motor neurons are lineal sister cells in the AB.p lineage. The VA motor neurons are required for backward movement and the VB motor neurons are required for forward movement. Mosaic analysis showed that the wild-type pag-3 gene is required in the AB.p lineage for coordinated movement and in the AB.a lineage to suppress touch neuron gene expression in the BDU neurons. Because pag-3 is expressed in both the BDU neurons and in the touch neurons, another protein(s) not expressed in the touch neurons may interact with pag-3 to repress touch neuron gene expression in the BDU neurons. Alternatively, another protein in the touch receptor cells may inactivate PAG-3 and allow expression of the touch receptor program. These results show that pag-3 is a temporally regulated gene that is expressed early in development and functions in multiple types of neurons. They also strongly suggest that the PAG3 protein is a DNA-binding protein with properties similar to the mammalian proto-oncogene product GFI-1.

The gfi-1 gene encodes a zinc finger containing protein that is specifically expressed in T-lymphocytes and is a frequent target of proviral insertion in T-cell lymphoma provoked by infection with MoMuLV--a non acute transforming retrovirus. expression of a gfi-1 transgene targeted to T-cells by the lck proximal promoter provokes a reduction of peripheral CD4 and CD8 positive T-cells but nevertheless weakly predisposes transgenic animals for the development of T-cell lymphoma. Forced coexpression of the serine/threonine kinase Pim-1 can partially restore normal T-cell numbers in double pim-1/gfi-1 transgenic mice. Moreover, the combinatorial expression of Pim-1 and Gfi-1 leads to accelerated development of T-cell lymphoma with a mean latency period of 114 days. A similar accelerated rate of lymphoma development was observed when lck-gfi-1 mice were crossed with mice that carry a L-myc gene targeted to be expressed at high levels in T-cells. The results show that gfi-1 can act with low activity as a dominant oncogene when overexpressed but also demonstrate that it is most efficient only in the presence of a cooperative partner protein as for example Pim-1 or L-Myc. In addition, the results suggest that Pim-1 and Gfi-1 are acting synergistically in both T-cell lymphomagenesis and T-cell development.