Disease relevance of GFI1

• Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2 [1].
• Electrophoretic mobility assays with nuclear extracts from prostate cancer cell lines established binding of GFI1 to the sequence 5'-TGGTACAATCATAACTCACTGCAG-3' present at -997 to -1200 in the repressive region [2].
• Here, we show that GFI1, as with ASH1, is expressed in neuroendocrine lung cancer cell lines and that GFI1 in lung cancer cell lines functions as a DNA-binding transcriptional repressor protein [3].
• Growth factor independence-1 is expressed in primary human neuroendocrine lung carcinomas and mediates the differentiation of murine pulmonary neuroendocrine cells [3].
• Growth-factor independence of a new differentiated hepatitis B virus DNA-negative human hepatoma cell line [4].

High impact information on GFI1

• 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].
• Here, we present experimental evidence implementing the zinc finger protein Gfi-1 as a new regulatory factor in STAT3-mediated signal transduction [5].
• Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes [6].
• Conversely, Gfi1 mRNA levels are high in granulocytes but the protein is swiftly degraded by the proteasome in these cells [6].
• Gfi1(-/-) mice exhibit a block in myeloid differentiation resulting in the accumulation of an immature myelo-monocytic cell population and the complete absence of mature neutrophils [6].

Chemical compound and disease context of GFI1

• Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells [2].

Biological context of GFI1

• 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 [1].
• GFI1 is upregulated in the earliest thymocyte precursors, while GFI1B expression is restricted to T lymphopoiesis stages coincident with activation [7].
• Importantly, GFI1 repression is dependent on an intact GFI1 binding site in the -997 to -1200 region [2].
• 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 [8].
• These EM(CD45RA+) IL-7Ralphalow cells were largely antigen experienced (CD27-CD28-), replicatively senescent (CD57+), and perforinhigh CD8+ T cells that had decreased IL-7Ralpha mRNA, independent of guanine and adenine binding protein alpha (GABPalpha) and growth factor independence-1 (GFI1) expression [9].

Anatomical context of GFI1

• Transgenic expression of GFI1 potentiates T-cell activation, while forced GFI1B expression decreases activation [7].
• Targeted transcriptional repression of Gfi1 by GFI1 and GFI1B in lymphoid cells [7].
• Upon forced monocytic differentiation of U937 cells, Gfi1 mRNA levels dropped but protein levels increased due to diminished proteasomal turnover [6].
• Silencing of Gfi1 expression in myeloid cells reverses G9a and HDAC1 recruitment to p21Cip/WAF1 and elevates its expression [10].
• Growth factor-independent activation of protein kinase B contributes to the inherent resistance of vascular endothelium to radiation-induced apoptotic response [11].

Associations of GFI1 with chemical compounds

• Growth factor independence of hematopoietic cells can be induced by ectopic expression of a variety of oncogenes encoding receptor or cytoplasmic tyrosine kinases [12].

Physical interactions of GFI1

• Site directed mutagenesis of the core GFI1 binding sequence (5'-AATC-3') substantially increased while forced expression of GFI1 decreased the expression of the CYP27B1 reporter construct [2].
• G9a and HDAC1 are both in a repressive complex assembled by Gfi1 [10].

Regulatory relationships of GFI1

• We found that Triad1 inhibited Gfi1 ubiquitination, resulting in a prolonged half-life [13].

Other interactions of GFI1

• Endogenous Gfi1 colocalizes with G9a, HDAC1, and K9-dimethylated histone H3 [10].

References